Publications

Pioneered by its founder, the late Dr Alan Howard, the Howard Foundation has supported over a decade of clinical trials led by Professor John Nolan at the Nutrition Research Centre Ireland (NRCI) of the Waterford Institute of Technology (WIT), into the benefits on visual and cognitive function of the three macular carotenoids, Lutein, Zeaxanthin, and Meso-zeaxanthin.

Starting in 2009, Dr Howard and Professor Nolan combined their skills and ideas to develop the Meso-zeaxanthin Ocular Supplementation Trials (MOST). The goal of this work was to examine the benefits of the addition of meso-zeaxanthin to the supplement formulation and to test this intervention on patients with AMD. These initial results using the three carotenoids were striking, and the benefits of including meso-zeaxanthin in the formulation were clear and many. Larger trials with longer duration of intervention followed, and the study expanded into other populations, including patients with Alzheimer’s disease and cognitive impairment. This continued work discovered that by combining the three carotenoids with omega-3 fatty acids, patients with Alzheimer’s disease benefited, with improvements seen in mood, memory and quality of life. This remarkable discovery is being examined further in the re-MIND trial which will conclude in 2021.  

These extensive research trials followed earlier research by Dr David Thurnham at the University of Ulster.

The Howard Foundation acknowledges the support from our industry partner, Industrial Organica (IOSA) of Mexico, who provided the supplements used in the interventional studies conducted by the NRCI. IOSA have developed a micro-micelle formulation which enhances both the stability and the bioavailability of the 3 carotenoids.

Further overview information on this work may be found on the Nutri-mz.health website.

Table of significant research papers

The table below shows the significant research papers and reviews that have been published relating to these studies. All the trials reported here were funded by the Foundation unless otherwise noted.

The list of papers can be arranged by either Year (Yr) or Topic & type of study by clicking the column heading. You can also click on the name of the paper in the right hand column to read the full paper in a new tab/window..

Yr Topic &
Type of Study
Description Paper
2007

Vision, AMD

Review

A review of dietary sources of the macular carotenoids and of their relationships with macular pigment density. The relative bioavailability of the carotenoids in different foods was examined. Egg yolk appears to be a rich and more bioavailable source of carotenoids in the diet than those in vegetables.  Some observations on the content of meso-zeaxanthin (MZ) in egg yolk in Mexico where chickens had been fed with an MZ-containing feed were reported, with implications for using mezo-zeaxanthin for macular pigment and AMD.

Macular zeaxanthins and lutein – a review of dietary sources and some relationships with macular pigment optical density and age-related macular disease.

Thurnham DI

Nutrition Research Reviews 2007:20:163-179

2008

Bioavailability

Human intervention, Single-Blind

This study in healthy adults looked at blood concentrations after a short term (21 days) trial giving a mixed supplement of three carotenoids (lutein, zeaxanthin and mezo-zeaxanthin). Blood was taken at baseline and days 10 and 22.  There was a progressive increase in concentration during the period of treatment. Blood concentrations of mezo-zeaxanthin in women were statistically higher than those in men at day 22.

This work represents an initial response study in humans.

A supplementation study in human subjects with a combination of meso-zeaxanthin, (3R,30R)-zeaxanthin and (3R,30R,60R)-lutein 

Thurnham DI, Tremel A, Howard AN

British Journal of Nutrition (2008), 100, 1307–1314 

2010

Vision 
(MOST)

Human Intervention, Single-Blind

This initial exploratory work with meso-zeaxanthin showed that humans respond both very well and very quickly to a supplement with the three macular carotenoids over 8 weeks. This experiment suggested that meso-zeaxanthin may offer advantages to a supplement formulation, but more work was needed.

This was the first study in the series of Meso-zeozanthin Ocular Supplementation Trials (MOST).

Augmentation of macular pigment following supplementation with all three macular carotenoids: an exploratory study.

 

Connolly EE, Beatty S, Thurnham DI, Loughman, J, Howard AN, Stack J, Nolan JM.

Current Eye Research 2010;35:335-351

2010

Vision

Human, Discovery

This experiment discovered that about 12% of the population (sampled from Ireland) have atypical central dips in their macular pigment. Of interest, these individuals had increased risk of age-related macular degeneration (because of their risk factors). John Nolan hypothesised here that the dips in central macular pigment were uniquely due to a deficiency of meso-zeaxanthin in these individuals because this is where meso-zeaxanthin is concentrated in the macular pigment.

This trial was supported by the Medical Research Charities Group Grant, through Fighting Blindness, Ireland and the Health Research Board, Ireland

A Central Dip in the Macular Pigment Spatial Profile is Associated with Age and Smoking.

 

Kirby ML, Beatty S, Loane E, Akkali M, Connolly E, Stack J, Nolan JM.

Investigative Ophthalmology &  Visual Science 2010.

2011

Vision
(MOST-N)

Human Intervention, Single-Blind, Placebo-Controlled

This experiment followed healthy participants over a 6 month period to again examine their response to the three carotenoids in their blood and eyes. Importantly, this re-confirmed an exceptional response when using the three carotenoids in a supplement formulation. Also, detailed testing of safety measures showed no adverse clinical implications of consuming these carotenoids.

This was the second publication  in the series of Meso-zeozanthin Ocular Supplementation Trials (MOST).
.

Supplementation with all three macular carotenoids: response, stability, and safety.

 

Connolly EE, Beatty S, Loughman J, Howard AN, Louw MS, Nolan JM.

Investigative Ophthalmology &  Visual Science 2011;52:9207-9217.

2012

Vision

Human Intervention, Single-Blind, Placebo-Controlled

These results showed that, in healthy individuals,  supplementation with all three macular carotenoids offered advantages over preparations lacking meso-zeaxanthin, both in terms of macular pigment response and visual performance enhancement (contrast sensitivity with and without glare). This work generated excitement in that this formulation may be a way to enhance vision for the general population The impact of macular pigment augmentation on visual performance using different carotenoid formulations.

 

Loughman J, Nolan JM, Howard AN, Connolly E, Meagher K, Beatty S.

Investigative Ophthalmology & Visual Science 2012;53:7871-7880.

2012

Vision

Human Intervention, Single-Blind, Placebo-Controlled

This research discovered how to fix (rebuild) the central macular pigment in participants with a central dip in their macular pigment. The previous hypothesis from John Nolan that meso-zeaxanthin would provide the solution was confirmed, as the only formulation to achieve the desired result had meso-zeaxanthin as part of the formulation. This is a landmark study, claimed by Dr Alan Howard as a major discovery of our time.  Macular carotenoid supplementation in subjects with atypical spatial profiles of macular pigment. 

 

Nolan JM, Akkali MC, Loughman J, Howard AN, Beatty S.

Experimental Eye Research 2012;101:9-15.

2013

Vision, AMD

Human Intervention, Single-Blind, Placebo-controlled

This was a detailed study of the bioavailability of carotenoid response in blood. The formulation containing all three macular carotenoids was the most effective in terms of achieving the highest combined concentration of these carotenoids in blood, thereby potentially optimising the bioavailability of these compounds for capture by the target tissue (retina).

Funding was provided by the European Research Council (ERC).

Serum response to supplemental macular carotenoids in subjects with and without age-related macular degeneration.

 

Meagher KA, Thurnham DI, Beatty S, Howard AN, Connolly E, Cummins W, Nolan JM.

British Journal of Nutrition 2013;110:289-300.

2013

Vision, Discovery

Review

This was a detailed scientific review of meso-zeaxanthin, where it comes from and why it is important for eye health and function. This work corrected some misconceptions relating to meso-zeaxanthin. What is meso-zeaxanthin, and where does it come from?

 

Nolan JM, Meagher K, Kashani S, Beatty S.

Eye (Lond) 2013;27:899-905.

2014

Methodology (CREST)

Protocol published before trial commenced

This paper described the protocol for the gold standard, Central Retinal Enrichment Supplementation Trials (CREST) study.  

CREST was the first study to investigate the impact of supplementation with all three macular carotenoids in the context of a large, double-blind, randomized clinical trial.

Publishing the protocol before the trial began was important as it ensured that there was no bias in either the experiment or the presentation of the results. The paper presented the main populations of interest, the interventions to be used and the primary outcome measures. This meant that the researchers could not change the research questions or research outcomes.

The trials were funded by the European Research Council (ERC). The design was informed from the work on the earlier MOST projects, sponsored by the Howard Foundation.

Central Retinal Enrichment Supplementation Trials (CREST): design and methodology of the CREST randomized controlled trials.

 

Akuffo KO, Beatty S, Stack J, Dennison J, O’Regan S, Meagher K, Peto T, Nolan JM.

Ophthalmic Epidemiology 2014;21:111-123.

2014

Alzheimer’s (CARDS 1)

Human, Cross-Sectional

This work, the Carotenoids and Age- Related Dementia Study (CARDS) represented the first discovery for Alzheimer’s disease relating to carotenoids. The research discovered that patients with Alzheimer’s disease are deficient in carotenoids and have poorer vision when compared to age-matched controls.

Based upon these results, it was proposed to investigate the impact of the three carotenoids on macular pigment, visual and cognitive function in subjects with Alzheimer’s disease.

Macular Pigment, Visual Function, and Macular Disease among Subjects with Alzheimer’s Disease: An Exploratory Study;

 

Nolan J, Loskutova E, N Howard A, Moran R, Mulcahy R, Stack J, Bolger M, Dennison J, Akuffo K, Owens N, Thurnham DI, Beatty S.

Journal of Alzheimer’s Disease 2014 1191-1202.

2014

Vision, AMD (MOST 1)

Human Intervention, Single-Blind, Head-to-Head

This study, the Meso-zeozanthin Ocular Supplementation Trial (MOST), showed that the formulations containing the three carotenoids resulted in improvements in visual function for patients with early age-related macular degeneration (AMD). It showed that measuring contrast sensitivity (the ability to distinguish the foreground from the background) is a very good way to demonstrate these improvements. 

This paper showed results after 12 months supplementation. Further results are shown in the 2015 paper as MOST 2.

Supplementation with three different macular carotenoid formulations in patients with early age-related macular degeneration.

 

Sabour-Pickett S, Beatty S, Connolly E, Loughman J, Stack J, Howard AN, Klein R, Klein B, Meuer S, Myers C, Akuffo K, Nolan JM.

Retina 2014;34:1757-1766.

2014

Nutrition

Analytical, Discovery

This work showed the presence of meso-zeaxanthin in fish and that it may be consumed (in small quantities) as part of the human diet.  Verification of Meso-zeaxanthin in Fish.

 

Nolan JM, Beatty S, Meagher KA, Howard AN, Kelly D, Thurnham DI.

Journal of Food Processing and Technology 2014b;5:335.

2014

Vision

Human Intervention, Single-Blind, Head-to-Head

This research investigated the impact of different amounts of the three carotenoids.  This important study showed that the concentrations of meso-zeaxanthin in blood were strongly correlated with macular pigment after 8 weeks of supplementation with this carotenoid. The inclusion of lutein was also important to ensure a full response in macular pigment. Macular response to supplementation with differing xanthophyll formulations in subjects with and without age-related macular degeneration.

 

Thurnham DI, Nolan JM, Howard AN, Beatty S.

Graefes Arch Clin Exp Ophthalmol 2014.

2015

Vision, AMD (MOST 2)

Human Intervention, Single-Blind, Head-to-Head

This study continued the research from MOST 1. It followed subjects for 3 years. It showed that the longer the period of supplementation, the better the outcome for patients with early age-related macular degeneration. It highlighted the importance of continued supplementation for vision and retinal health. Sustained supplementation and monitored response with differing carotenoid formulations in early age-related macular degeneration.

 

Akuffo KO, Nolan JM, Howard AN, Moran R, Stack J, Klein R, Meuer SM, Sabour-Pickett S, Thurnham DI, Beatty S.

Eye (Lond) 2015;29:902-912.

2015

Cognitive Function (CREST)

Cross-Sectional

This is the first report from the Central Retinal Enrichment Supplementation Trials (CREST). The research demonstrated that macular pigment measurements provide a good indicator for cognitive health (memory and attention) in participants with no eye disease or brain disease (the healthy population).

This was the first study in which the team used a computerized software program to assess cognitive response in subjects.

Cognitive Function and Its Relationship with Macular Pigment Optical Density and Serum Concentrations of its Constituent Carotenoids.

 

Kelly D, Coen RF, Akuffo KO, Beatty S, Dennison J, Moran R, Stack J, Howard AN, Mulcahy R, Nolan JN.

Journal of Alzheimer’s Disease 2015;48:261-277.

2015

Alzheimer’s (CARDS 2)

Human Intervention, Double-Blind, Placebo-Controlled

This study, the second Carotenoids and Age-Related Dementia Study (CARDS) showed that patients with Alzheimer’s disease respond positively to the supplement formulation with the 3 carotenoids. It demonstrated improvements in carotenoids in blood, retina and in visual function for these patients.

These results prompted further study to look at the impact of supplementation on cognition and visual function in subjects with Alzheimer’s disease over a longer period of time.

The impact of supplemental macular carotenoids in Alzheimer’s disease: a randomized clinical trial

 

Nolan JM, Loskutova E, Howard AN, Mulcahy R, Moran R, Stack J, Bolger M, Coen R, Dennison J, Akuffo K, Owens N, Power R, Thurnham DT, Beatty S.

Journal of Alzheimer’s Disease 2015;44:1157-1169.

2016

Vision, AMD

Review

This review article first examines the chemistry, biochemistry, biophysics, and physiology of the yellow pigments that are specifically concentrated in the macula lutea through the means of high-affinity binding proteins and specialized transport and metabolic proteins where they play important roles as short-wavelength (blue) light-absorbers and localized, efficient antioxidants in a region at high risk for light-induced oxidative stress. Next, it turns to clinical evidence supporting functional benefits of these carotenoids in normal eyes and for their potential protective actions against ocular disease from infancy to old age.

Lutein, zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease.

Bernstein PS, Li B, Vachali PP, Gurusupudi A, Shyam R, Henriksen BS, Nolan JM

Progress in Retinal and Eye Research 50 (2016) 34-66

2016

Vision (CREST)

Human Intervention, Double-Blind, Placebo-Controlled

This is the second report from the Central Retinal Enrichment Supplementation Trials (CREST). It confirmed that supplementation with the formulation using the 3 carotenoids improves visual function for adults in the general population with low macular pigment.

It demonstrated a way to maximize visual performance and experience, whether for professional or leisure activities.

The trial used a data and safety monitoring committee consistent with the highest quality of trial design.

Enrichment of Macular Pigment Enhances Contrast Sensitivity in Subjects Free of Retinal Disease: Central Retinal Enrichment Supplementation Trials – Report 1.

 

Nolan JM, Power R, Stringham J, Dennison J, Stack J, Kelly D, Moran R, Akuffo K, Corcoran L, Beatty S..

Investigative Ophthalmology & Visual Science 2016;57:3429-3439.

2016

Bioavailability

Animal Intervention, Placebo-Controlled

This research demonstrated a way to enrich the carotenoid concentrations in the egg yolks of hens. Additionally, the greatest responses used a novel carotenoid formulation (known as micro-micelle). Lutein, zeaxanthin and meso-zeaxanthin content of eggs laid by hens supplemented with free and esterified xanthophylls.

 

Nolan JM, Meagher KA, Howard AN, Moran R, Thurnham DI, Beatty S.

Journal of Nutritional Science 2016;5:e1.

2017

Vision, AMD (CREST)

Human Intervention, Double-Blind, Head-to-Head

This is the third report from the Central Retinal Enrichment Supplementation Trials (CREST). It confirmed that supplementation over 24 months with the formulation using the 3 carotenoids improves visual function for patients with early stage age-related macular degeneration (AMD).

This was a major finding because these patients normally lose their visual function and this confirmed that they can improve their function using supplementation with the 3 carotenoids.

The trial used a data and safety monitoring committee consistent with the highest quality of trial design.

The Impact of Supplemental Antioxidants on Visual Function in Nonadvanced Age-Related Macular Degeneration: A Head-to-Head Randomized Clinical Trial.

 

Akuffo KO, Beatty S, Peto T, Stack J, Stringham J, Kelly D, Leung I, Corcoran L, Nolan JN.

Investigative Ophthalmology & Visual Science 2017;58:5347-5360.

2017

Vision (EXIT)

Human Intervention, Single-Blind, Head-to-Head

The Egg Xanthophyll Intervention clinical Trial (EXIT) demonstrated that consumption of the carotenoid rich eggs greatly improved blood carotenoid levels but the duration of supplementation (8 weeks) was not long enough to improve macular pigment or visual function levels. Serum and macular response to carotenoid-enriched egg supplementation in human subjects: the Egg Xanthophyll Intervention clinical Trial (EXIT).

 

Kelly D, Nolan JM, Howard AN, Stack J, Akuffo K, Moran R, Thurnham DI, Dennison J, Meagher K, Beatty S.

British Journal of  Nutrition 2017;117:108-123.

2018

Alzheimer’s (CARDS 3)

Human Intervention, Single-Blind, Head-to-Head

This landmark paper identified that combining the carotenoids with omega-3 fatty acids is beneficial for patients with Alzheimer’s disease.

This formulation gave a greater carotenoid improvement in blood and also provided improvements in the quality of life for patients with Alzheimer’s disease.

This preliminary report suggested that due to the small number of patients, further study should be carried out.

Nutritional Intervention to Prevent Alzheimer’s Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined.

 

Nolan JM, Mulcahy R, Power R, Moran R, Howard AN.

Journal of Alzheimer’s Disease 2018;64:367-378.

2018

Cognitive Function 
(CREST)

Human Intervention, Double-Blind, Placebo-Controlled

This study showed, for the first time, that supplementation with the 3 carotenoids in the healthy population improves cognitive function by improving memory.

A major strength of this study rests on its design. CREST was a double-blind, randomized clinical trial, where neither the subjects nor researchers knew which individuals were consuming the active supplement and which subjects were consuming the placebo, and where allocation to the active treatment or placebo was randomized.

This was an important discovery for people in society that want to support brain health.

The trial used a data and safety monitoring committee consistent with the highest quality of trial design.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

 

Power R, Coen RF, Beatty S, Mulcahy R, Moran R, Stack J, Howard AN, Nolan JN

Journal of Alzheimer’s Disease 2018;61:947-961.

2019

Alzheimer’s Cognitive Function

Major Review

This paper was a major review to discuss and present all the available information relating to targeted nutrition using omega-3 fatty acids and carotenoids for brain health.

Given their selective presence in the brain and their ability to slow down the development of Alzheimer’s disease (namely oxidative damage and inflammation), these nutritional compounds offer potential for optimizing cognition and reducing the risk of Alzheimer’s disease.

The Role of Nutrition for the Aging Population: Implications for Cognition and Alzheimer’s Disease.

 

Power R, Prado-Cabrero A, Mulcahy R, Howard AN, Nolan JM.

Annual Review of Food Science and Technology 2019;10:619-639.

2020

Bioavailability

Human Intervention, Single-Blind, Head-to-Head

This work represents the newest discovery by the research team. Here they identified a way to enhance the stability and bioavailability of the 3 carotenoids using a micro-micelle formulation.

This trial was funded by the Howard Foundation, via the Waterford Institute of Technology (WIT) President’s scholarship program, in partnership with Industrial Organica, Mexico who provided the supplements used in the trial.

The Impact of Formulation on Lutein, Zeaxanthin, and meso-Zeaxanthin Bioavailability: A Randomised Double-Blind Placebo-Controlled Study.

 

Green-Gomez M, Prado-Cabrero A, Moran R, Power T, Gomez-Mascaraque L, Stack J, Nolan JM

Antioxidants (Basel) 2020;9.

2020

Alzheimer’s (CARES 1)

Human Intervention, Double-Blind, Placebo-Controlled

The Cognitive impAiRmEnt Study (CARES) is another important interventional study using the 3 carotenoids combined with omega-3 fatty acids to improve brain health.

The population studied here had an early stage of Alzheimer’s disease known as mild cognitive impairment (MCI). The supplement intervention improved their memory function using the 3 carotenoids and omega-3 combined.

Strengths of CARES trial 1 include a comprehensive assessment of MCI using sensitive and validated diagnostic measurement tools at screening, enrolment and follow-up assessments. Also the use of a consensus panel provided in-depth characterization of all the individuals taking part in the trial.

Targeted Nutritional Intervention for Patients with Mild Cognitive Impairment: The Cognitive impAiRmEnt Study (CARES) Trial 1.

 

Power R, Nolan JM, Prado-Cabrero A, Coen R, Roche W, Power T, Howard AN, Mulcahy R.

Journal of Personalized Medicine 2020;10.