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    Why AMD supplementation should not be casual

    Prescribing supplements for AMD should rely on science, not chance

    I disagree with an ongoing claim that supplementation with three retinal carotenoids is superior to supplementing with only two dietary carotenoids.1

    For clinicians who prescribe supplements other than Age-Related Eye Disease Study (AREDS) II for high-risk age-related macular degeneration (AMD) patients or consider prescribing the same carotenoid components for low- and moderate-risk AMD patients, the recent CREST 2 study (Central Retinal Enrichment Supplementation Trial) data may be instructive.2

    What CREST 2 tells us

    CREST 2 evaluated the impact of supplementation with all three macular carotenoids (Lutein [L]; zeaxanthin [Z], meso-zeaxanthin [MZ]) in early AMD.3 RS MZ is important because, along with its dietary isomer RR Z, it is found only in the fovea. MZ is not present in any other ocular or systemic tissue, including skin and brain, and there is no common dietary source.

    Previously from Dr. Richer: ODs’ role promising in detecting Alzheimer’s disease

    CREST 2 was a two-year, randomized, double-blind, controlled study that evaluated a lower 25 mg zinc (Zn)/AREDS II formulation vs. 25 mg Zn/AREDS II + 10 mg MZ in minimal risk AMD patients. The single clinical site study originates from carotenoid scientists at the Macular Pigment Research Group in Ireland, a country where AMD is a huge public health concern.4

    CREST 2 outcome

    The primary CREST 2 outcome measure was letter contrast sensitivity (CS) at six cycles per degree—which is different from the high spatial frequencies typically employed during routine eye exams. CS, not visual acuity, is closer to how patients see in everyday life.

    CREST 2 showed no difference in this primary outcome (p=0.88). The global improvement in CS and each of the secondary measures of visual function were virtually identical with or without the addition of 10 mg synthetic MZ.

    Paul Bernstein, MD, PhD, and his team at the Moran Institute in Salt Lake City, UT, have looked at both transporter and retinal blinding proteins for the three retinal carotenoids. They have also demonstrated the ubiquitous retinal enzyme RPE65 is responsible for the conversion of L to MZ in vertebrates, implying that MZ is readily available to those who supplement with L.5, 6

    Related: Details matter when prescribing meso-zeaxanthin

    This is a unique role for RPE65 beyond its well-known isomerization of all-trans-retinyl esters to 11-cis-retinol in the vertebrate visual cycle.6 The conversion occurs in the retinal pigment epithelium (RPE).7 L is now so important for eye and brain health that a new publication calls for the establishment of a Dietary Reference Intake (DRI).8

    Carotenoid competition

    Careful examination of CREST 2 data shows depression of serum L, Z, and total carotenoids despite a near doubling the carotenoid supplementation with an enriched 10 mg MZ + AREDS II carotenoids formula.

    The difference between the two formulations was statistically significant for serum Z levels (p=0.005). This is potentially concerning because dietary L and Z have recently emerged as crucial, if not essential, brain nutrients.9,10

    Finally, I disagree with the statement, “Triple carotenoid formulas are essential for normalizing atypical central dips in macular pigment spatial profiles.”1 Our laboratory has published evidence to the contrary.11

    Dietary Z is capable of normalizing central foveal macular pigment dips. It is likely 2 mg of dietary Z employed within AREDS II was not adequate—especially considering the 1:1:1 ratio of L:Z:MZ found in the human fovea.

    Noteworthy is another study from practicing optometrists. In a their large clinical study, three optometrists showed drusen can disappear with an ocular supplement containing only 8 mg dietary Z and 4 mg L.12 In my opinion, this study also negates the suggestion that three carotenoids are necessary.



    1. Dierker D. What Are Carotenoids — And Are Two of Them Enough? Optometric Management. Available at: https://www.optometricmanagement.com/newsletters/nutritional-insights-for-clinical-practice/november-2017. Accessed 1/11/18.

    2. Akuffo KO, Beatty S, Peto T, Stack J, Stringham J, Kelly D, Leung I, Corcoran L, Nolan JM. The Impact of Supplemental Antioxidants on Visual Function in Nonadvanced Age-Related Macular Degeneration: A Head-to-Head Randomized Clinical Trial. Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5347-5360.

    3. Centres and Groups Macular Pigment Research Group. Waterford Institute of Technology. Available at: https://www.wit.ie/research/centres_and_groups/research_groups/science/macular_pigment_research_group. Accessed 1/11/18.

    4. Akuffo KO, Nolan J, Stack J, Moran R, Feeney J, Kenny RA, Peto T, Dooley C, O’Halloran AM, Cronin H, Beatty S. Prevalence of age-related macular degeneration in the Republic of Ireland. Br J Ophthalmol. 2015 Aug;99:1037–1044.

    5. Shyam R, Vachali P, Gorusupudi A, Nelson K, Bernstein PS. All three human scavenger receptor class B proteins can bind and transport all three macular xanthophyll carotenoids. Arch Biochem Biophys. 2017 Nov 15;634:21-28

    6. Shyam R, Gorusupudi A, Nelson K, Horvath MP, Bernstein PS. RPE65 has an additional function as the lutein to meso-zeaxanthin isomerase in the vertebrate eye. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10882-10887.

    7. Gorusupudi A, Shyam R, Li B, Vachali P, Subhani YK, Nelson K, Bernstein PS. Developmentally Regulated Production of meso-Zeaxanthin in Chicken Retinal Pigment Epithelium/Choroid and Retina. Invest Ophthalmol Vis Sci. 2016 Apr;57(4):1853-61.

    8. Ranard KM, Jeon S, Mohn ES, et al. Dietary guidance for lutein: consideration for intake recommendations is scientifically supported. Eur J Nutr. 2017 Dec;56(Suppl 3):37-42.

    9. Vishwanathan R, Neuringer M, Snodderly DM, Schalch W, Johnson EJ. Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates. Nutr Neurosci. 2013 Jan;16(1):21-9.

    10. Hoffmann KG, Richer SP, Wrobel JS, Chen E, Podella CJ. Prospective Study of Neuro-Cognitive Enhancement with Carotenoids in Elderly Adult Males with Early Age Related Macular Degeneration, Ophthalmology Research: An International Journal. 2015. 4(1):1-8.

    11. Richer SP, Cebold B, Katkar M, Huntjens B, Pratt SG, Stiles W, Ulanski L, Gierhart D. Restoration of Central Macular Pigment Dip with Dietary RR Zeaxanthin Supplementation in Patients with AMD. Adv Ophthalmol Vis Syst. 7(3): 00219.

    12. Herman JP, Kleiner-Goudey SJ, Davis RL. Case Report of Dietary Supplements Improving Macular Pigment and Visual Function. Adv Ophthalmol Vis Syst. 6(1): 00166.

    Read more from Dr. Richer here

    Stuart Richer, OD, PhD, FAAO
    Stuart Richer, OD, PhD, FAAO, is director of ocular preventive medicine at James Lovell Federal Health Care Facility in Chicago. He is ...

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    • Anonymous
      Stu Richer really loves tooting his horn, that is, when he's not running a hatchet job on Meso-Z. So here's an excerpt of results from his ZVF Study (he was first author), often used to promote RR-Zeaxanthin by the company he consults for (btw, I didn't see any disclosure statements for this article- hmm). From ZVF Results, "In the Zx group, detailed high-contrast visual acuity improved by 1.5 lines, Retina Foundation of the Southwest shape discrimination sharpened from 0.97 to 0.57 (P=0.06, 1-tail), and a larger percentage of Zx patients experienced clearing of their KVF central scotomas (P=0.057). The ‘‘Faux Placebo’’ L group was superior in terms of low-contrast visual acuity, CSF, and glare recovery, whereas Zx showed a trend toward significance." From ZVF Conclusions, "The equally dosed (atypical dietary ratio) Zx plus L group fared worse in terms of raising MPOD, presumably because of duodenal, hepatic-lipoprotein or retinal carotenoid competition." This appears to be promotion of non-significant results, especially when derived from a loaded one-tailed test, a statistical slight of hand. Shame. However, Richer is quoted by reporter Annie-Rose Harrison-Dunn in Nutraingredients.com at the European Vitafoods Conference 2014 saying, "a series of impressive publications from the likes of the Waterford Institute in Ireland had shown, categorically, that meso builds pigment in the retina." Another bone to pick is his repeated line about "synthetic meso-Z". To clarify, MZ is created from marigold lutein using an isomerization process that is fundamentally the same as the extraction process of lutein, only at a higher temp and for longer time to make the conversion. Meanwhile, the company he consults for holds 7 patents specifying "zeaxanthin synthesized by... genetically engineered... Flavobacterium multivorum", known internationally as infectious agents and food spoilage bacteria. See US Patent #5747544

    Optometry Times A/V