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Doctors of Optometry | Course Notes

B6 OD – 1CE Macular Carotenoids: Effects in the Eye and Beyond (old title was The Benefits of Enriching Macular Pigment) Supported with an unrestricted education grant by MacuHealth

Sunday, February 18, 2018 7:00 am – 7:55 am Balmoral – 3rd Fl

Presenter: Dr. James M. Stringham Dr. Stringham earned his doctoral degree in experimental psychology from the University of New Hampshire in 2003. During postdoctoral appointments at the Schepens Eye Research Institute at Harvard Medical School and the Medical College of Georgia, he conducted research on ocular lutein, age‐related macular degeneration, the effects of intense light on visual performance, and plasticity of the visual system. Dr. Stringham then took a position as a visiting assistant professor at the University of Georgia, where he continued and extended a research program involving lutein and many facets of visual performance. In 2007, he became a senior vision scientist in the Air Force Research Laboratory (AFRL), where he was involved in extensive testing of the effects of lutein and zeaxanthin on human visual performance. Currently he is a research scientist at the University of Georgia, where his research includes studying the effects of lutein, zeaxanthin, and mesozeaxanthin on a variety of human physiological, health, and performance parameters.

Course Description

Learn about the importance of ocular nutrition through level 1 studies and how enriching macular pigment can improve visual performance including visual-motor skills, latent inhibition, and cognition. Also, how a fortified macular pigment can protect against oxidative stress, one of the leading causes of age-related macular degeneration. MacuHealth with LMZ3 is clinically proven to rebuild and fortify macular pigment efficiently and effectively as it includes all three of the critical carotenoids which comprise macular pigment.

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Doctors of Optometry | Course Notes

NOTES:

James M. Stringham, Ph.D.Visual Performancee Laboratoryl Perform

Dukemancee aborLaorm

e Eye CenterDukeDukeee ye Centerye CeenterentEyEyDepartment of Ophthalmology

Air Force Research Laboratoryorce Research LaborSan Antonio, TX

Macular Carotenoids: Effects in the Eye and oids: EffecBeyond

The macula a luteaa (“yellow spot”)

Malinow et al, 1980

Courtesy: : Snodderlyy DM, M, Aurann JD, D, Deloriri FC (1984) IOVS 25, 67474-4-685

Dietary consumption of foods (e.g. leafy-green vegetables and other colored fruits and veggies) that contain lutein & zeaxanthin leads to deposition in highly specific, vulnerable tissues.

• Retina• The yellow pigment seen is an accumulation of lutein and

zeaxanthin. Mesozeaxanthin converted from lutein (1:1:1 ratio). • Yellow absorbs potentially harmful blue light• L & Z are potent antioxidants, anti-inflammatories

• L & Z therefore protect the retina from photochemical damage and oxidative stress.• Leads to significant reduction in risk for developing AMD,

and slowed progression of AMD (Akuffo et al. 2018)

Agege-e-related Macular Degeneration (AMD)

• Higher macular pigment = significantly reduced risk for developing / progression of AMD* (e.g. Seddon et al. 1994).

• Increasing MPOD appears to slow the progression of AMD, and improve visual performance (Akuffo et al. 2017, in process)

• AMD, a progressive degeneration of central vision (macula) is “a leading cause of blindness in people over 55” in the U.S. (NIH)

Craft et al, 2004; Johnson, 2013.C

Frontal lobe

Temporal lobe

Hippocampus

Occipital cortex

L, Z, & MZ: Found Throughout Brain Tissue in Infants and Adults

Carotenoid concentration in the brain (mean of 4 brain regions; age 00-0-1 yrs)

0

10

20

30

40

50

60

Mea

n br

ain

caro

teno

id c

once

ntra

tion

(pm

ol/g

)

Lutein Zeaxanthin Crypto -Car Lycopene

*

**Significantly different from all other carotenoids at p<0.05.

Vishwanathann R, et al. l. Acta a Biologicaa Cracoviensiaa 2011;153 (3 (supplpl 1). Abstract 1.23

1. Hassevoortrt K, et al. Presented at: 45th Society for Neuroscience Annual Meeting; October 177-7-21, 2015; Chicago, IL.1.2.

Hassevoorrt K, et al. Presented at: 45th Society for Neuroscience Annual Meeting; October 1K 77 1, 2015; Chicago, IL.212Stringham NT, Stringham JM (2017). Presented at the International Carotenoid Society Meeting; Lucerne, Switzerland.

MPOD Is Positively Correlated With Memory in Positively Correlated With Memory in Preadolescent Children

•• Children with higher Children with higher Cmacular pigment density macular pigment densmacular pigment densperformed better at performed beperformed bettermemory tasks (

tttters (s (P

atatr ar aterter((PP=0.01)1)1 1

•• *Same type of relationship Same typfound in

e of relationstypn n young adultsss2

100%

95%

90%

85%

80%

75%

70%---0.5 0 0.25 0.5 0.75

MPOD

r=0.36P=0.01

Correlation between macular pigment Correlation between macular pigmentand memory in preadolescent childrennn1

1

Aver

age

Mem

ory

Succ

ess

MPOD & Cognitive Performance in Young, Healthy Adults?VERY recently, it was shown that supplementation with L & Z leads to significant improvement in several cognitive VERY recentlydomains in

y, it was shown that suntlyn n young, healthy adults

pt sutsts:

• Verbal memory•

Verbal memoryComprehensive memory

•Comprehensive meProcessing speed

•Processing speedPsychomotor speed

…all improved significantly…all improved significanwith 6 months of L/Z with 6 months of L/supplementation.

Because this was a doublele-e-blind, placebobo-Because this was a doubllee ind, placebblb bocontrolled trial, we can now suggest that controlled trial, we can now suggest that supplementation with L/Z makes the brain supplementation with L/Z makes the bramore efficient (not an effect of neural more efficient (not an effprotection necessarily)

• At the very least, it appears that diets deficient in L/Z compromise cognitive function•

At the very least, it appears that diets deficient in L/Z compromise cAnd even young, “healthy” brains can be optimized with nutrition

Stringham JM (2017). Proceedings of the International Carotenoid Society Meeting

Processing speed Sustained attention Composite memory-10

-8

-6

-4

-2

0

2

4

6

8

10

12

**

Placebo (n = 10) Supplement group (n = 49)

Cha

nge

in s

core

(12

mon

ths)

*Change in performance over 12 Change in performance over 12 months for three cognitive domains; months for three cognitive domains;Placebo group vs. combined macular Placebo group vs. combined macucarotenoid supplement groups. carotenoid Means +/

oid +/+/-

supplement groups.sid //-- SEM. Asterisk indicates Means ++// EM. Asterisk indicates SS

statistically significant difference vs. statistically significanplacebo (p < 0.05).

Cognition improved in young (18-25 yrs.), healthy adults:

From Stringham et al. (2017) [in process]

Lutein and DHA improved memory, learning, and executive improved memory, learningfunction in older women

• 12mg lutein and/or 800mg DHA improved– Memory scores– Verbal fluency – Rate of learning

Johnson, et al. Nutr Neurosci. 2008 Apr;11(2):75-83

10

Normal Subjective memory complaints MCI0

20

40

60

80

100

120

140

160

180

pico

mol

es /

gram

Cognitive Status

LuteinZeaxanthinCryptoxanthinBetaCaroteneLycopene

From Johnson et al. 2013. Journal of Aging Research

Carotenoid concentrations in the brain, for those 80 0 –– 100 years concentrations in the brain, for those 800old, as a function of cognitive status:

n = 5

n = 7n = 11

*

*

Carotenoids in the Brain Preserve Cognitive PerformanceRecently, a significant association between the level of L & Z in the eye (a proxy for brain levels) and Recently, a significant association between the level of L & Z in tcognitive performance in advanced age has been established.

Macular pigment (ocular L & Z) concentrations were Macular pigment (ocular L & Z)significantly associated with:

1. Better global cognition1.2.

Better global cognitionBetter verbal learning and fluency2.

3.Better verbal learning aBetter memory recall3.

4.Better memory recallFaster processing speed4.

5.Faster processing speedFaster perceptual speed

*Important point: Correlations were not determined Important point: Correlations were not determined between serum L/Z and cognition. Only retina / brain between serulevels. Long

serungng-

m L/Z and cognition. Only retina / brain umerugg--term accumulation in neural tissues is the key.

Vishwanathann et al. 2014. Age and Ageing; 43: 27171–1–275.

n = 108, n 177.6 +/

n 1+/+/-

08, 1 1//-- 2.7 years

Macular Carotenoid Status in Earlyly-y-Stage Alzheimer’s Macular CarotenoiDisease Patients:

• We now have enough data on the matter to substantiate the claim that regular consumption of L/Z has a significant We now have enough data on the matter to substantiate the claim that regular consumption of L/Z has a significaeffect on neural protection and disease process, which may manifest as improved cognition / vision in old age.

(from Nolan et al. 2015)

Early y –– stage Alzheimer’s disease patients Earlyy tage Alzheimer s disease patients sthave significantly lower MPOD, compared have significantly lowto normal controls

A metaphor: Effects of UV / blue light damage on skin

Image: www.boston.com

The gentleman pictured was a truck driver for 39 years. The left The gentleman pictured was a truck driver for 39 years. The left half of his face (nearest sun exposure; he often drove with his half of his face (nearest sun exposure; he often drove with hiswindow open) is markedly more aged than the right half).

s h his. The window open) is markedly m

point here is that we can mordly m

nn seere aged than the right half).. heThmor

ee effects of cumulative oxidative point here is that we cann eesee ffects of cumulative oxidativeefdamage on the skin. The same process, however, occurs within damage on the body

on yy –

he skin. The same process, howton – in places like the eye and brain

hown n –

ever, occurs within wew– where we cannot see the bodyy n places like the in

it…often until it is too late.

Macular carotenoids and screen time: The “Blue Light” StudyThe average American adult spends 11 hours / day in front of screens• Undesirable effects (e.g. eye strain, eye fatigue, headache) are very

common • Also…sleep disturbance. Can L/Z/MZ help?

From Stringham et al. 2017

• RDBPC trial in young, healthy adults• Some reporting 16-17 hours / day screentime(!)• Placebo vs. 24 mg L/Z/MZ (Lutemax 2020) daily

for 6 months• Examined physical indicators of high screen time• And sleep quality• Determined dramatic improvements in several

parameters• Improvement in physical symptoms may be due

to reduction in long-term, low-level squinting of the eyes

placebo 24 mg MC-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

n = 35

*

*

Perc

ent c

hang

e fro

m b

asel

ine

Headache Neck Strain Eye Strain Blurry Vision Eye Fatigue

*

n = 13

Blue light input from the eye helps to set circadian Blue light rhythm.rhy

•ythm.yth

MCs deposited in the eye, and absorb blue MCs deposited in the eye, and absorb bluelight. Sleep quality improvement would light. Sleep quality improvement would appear to be ocular effect. However…

•appear to be ocular effect. However……macular pigment is in central retina, …macular pigment is in central retina, receptors for circadian entrainment are in receptors foperiphery.

•periphery.So, sleep quality effect is probably not retinal, So, sleep quabut rather,

lity effect is probably nquar,r systemic reduction in but ratherr, ystesy

inflammation.•

inflammation.Less irritation, less tossing and turning

Sleep Quality Improvement

placebo 24 mg MC

-30

-25

-20

-15

-10

-5

0

5

10

Perc

ent c

hang

e fro

m b

asel

ine

(num

ber o

f sle

ep d

istu

rban

ces)

*

From Stringham et al. 2017

Significant reduction in number of sleep disturbances Significant reduction in number of sleep disturbancfound in MC supplementation group vs. placebo.

placebo 24 mg MC-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

n = 35

**

*

*

*

Perc

ent c

hang

e fro

m b

asel

ine

MPOD CFF DG PSR CS

n = 13

Visual performance results from the “Blue Light Study”

MPODD significantly increased, and MPODD ignificantly increased,siseveral parameters of visual several parameters of visual performance were found to improve:

• Speed of visual processing g (CFF)•

Speed of visual pDisability glare

processingg CF(Cal pee (DG): seeing Disability glaree D(D

“through” glare•

through glarPhotostress

reglarss recovery time e (PSR)

•Photostress ecovery reContrast sensitivity

timeeery y y (CS)

It is clear that increased MPOD leads to significant It is clear that increased MPOD leads to significantvisual performance enhancement in young adults.

The macular carotenoids have widede-e-ranging benefits for neural health and ve widdee anging baraperformance:

• Cognitive PerformanceCo•

ognitive PerformanceoAcross the lifespan!

•Acros

Neuralss the lifespan!cros

alal disease / diseases of Cognitive Decline:Ne•

euraal isedeAMD

•AMDDementia

•DementiaAlzheimer’s disease

•Alzheimer s disea

Visual PerformanceVis•

sual PerformancesSpeed of visual processing

•Speed of visual proceContrast sensitivity

•Contrast sensitivityFaster dark adaptation

•Faster dark adaptationVisual performance in glare

•Visual performance in glare

L, Z, and MZ: Necessary for health and performance across the lifespanL, Z, and MZ: Necessary for health and performance across the life*A great opportunity to discuss meaningful benefits with patientsA great opportunit*Optometry = the

y to discuss meaningfuunite e healthcare “interface”

l benefits with patigfu” for all of the above

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BACKUP SLIDES

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Safety / toxicity / tolerance of L, Z, and MZ?

• Generallyly-y-Regardeded-d-AsAsA -ss-Safe (GRAS) status granted by the FDA for lutein (2003) and Generallyyzeaxanthin

egardeeddeReRnn (2004).

•zeaxanthinn 2004).(2What about MZ?Wh

•at about MZ?a

Not as common in diet (trace amounts typical).•

Not as common in diet (trace amounts typical).Toxicity tests for MZ show ridiculously high toleranceTox

•icity tests for MZ show ridiculoic

The NOAEL (‘No Observedculo

eded-ously highoculo

dd--Adversehigh

sese-h tolerancehhigh

ee--Effect Level’) was in excess of 200 The NOAEL ( Nmg/kg/day (

No ObserveL ( Ny (y (Thurnham

eedd dversAdA see ffect LeEfErvemm & Howard, 2013).

•mg/kg/dayy ( hurnhamTh m & Howard, 2013). &

This is far greater than doses used in dietary supplements, which are typically This is far greater th~0.25 mg/kg/day. 0.2

•25 mg/kg/day. 2

Absence of mutagenicity was also confirmed in the same study. •

Absence of mutagenicity was also confirmed in the same sIn 2011, MZ was granted GRAS status by the FDA (Notice 000385).

•In 2011, MZ was granted GRAS status by the FDA (Notice 000385).Finally, a recent safety evaluation of MZ by Xu et al. (2013) concluded that MZ has no Finally, a recent safety eacute toxicity and no

evaluation ofety eoo genotoxicity

f n oftyty.acu

•te toxicity and noo enotoxiget

Additional conclusions:Add•ditional conclusions:di

The use of MZ is safe at doses of 300 mg/kg body weight per day in rats, The use of MZ isbased on a 90

MZ is9090-

safe at doses of 30s Z is00--day feeding study.

•based on a 9900 ay feeding study. dadThe authors then applied a 100 fold safety factor, and reported an ADI The authors then applied a 100 fold safety factor, and reported an (acceptable daily intake) of 3 mg/kg body weight per day for MZ.

• TAKEKE-(acceptable daily intake) of 3 mg/kg body weight per day for MZ.

E-HOME MESSAGE: The body can tolerate very high levels of L, Z, and MZ.

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