Understanding Circadian Responses to Light in Persons With Mild Cognitive Impairment and Alzheimer's Disease
Phase: NA
Conditions: Mild Cognitive Impairment, Alzheimer Disease
Sponsor: Icahn School of Medicine at Mount Sinai

Understanding Circadian Responses to Light in Persons With Mild Cognitive Impairment and 
Alzheimer's Disease
PI: Mariana Figueiro, PhD
NCT05411822
Document Date: 4/20/2021

SPECIFIC AIMS (resubmission revisions marked in italics) 
In 2019, the estimated total cost associated with ADRD in the United States was $234 billion, which is expected 
to balloon to $1.1 trillion by 2050, according to the latest (2019) estimates by the Alzheimer’s Association. 2 Ap-
proximately 40% of the estimated 5.5 million older (65+) Americans with Alzheimer's disease and related de-
mentias (ADRD) suffer from severe dysfunction of their sleep-wake and circadian systems, manifesting clini-
cally as sundowning, excessive daytime sleepiness, nocturnal wandering, agitation, and day-night reversal. 3,4 
In people with mild cognitive impairment (MCI), an “at risk” or potential prodromal stage of dementia, sleep-
wake disturbance is evident in up to 60% of patients. 5,6  
The daily pattern of light and dark reaching our retinas is the primary zeitgeber that regulates distinct biologi-
cal processes by setting the timing of the endogenous circadian pacemaker in the suprachiasmatic nucleus 
(SCN) in accordance with Earth’s 24-h solar day. Melatonin is produced by the pineal gland at night in dark 
conditions and is known as the “darkness hormone.” In humans, melatonin is used as a marker of the timing 
of the biological clock and its production is ceased by exposure to light at night, which is one of the main rea-
sons melatonin is used as an outcome measure in experiments designed to understand circadian phototrans-
duction mechanisms in humans.7,8 Circulating melatonin levels change in a graded manner to variations in 
spectrum, amount, distribution, duration, and timing of light exposure. It is therefore imperative that a com-
plete understanding of these lighting characteristics be developed so that: (1) the most effective lighting is used 
for therapy and (2) the most appropriate and effective light is installed in buildings. The latter application is 
particularly significant because senior housing lighting is typically dim and constant, which could be a reason 
why sleep disturbances are so much more common in older adults, including those with Alzheimer’s disease 
and related dementias (ADRD) who are living in more controlled environments. Much is already known about 
the absolute and spectral sensitivities9,10,11 of acute melatonin suppression, but not much attention has been 
given to the effect of light's spatial characteristics (distribution) and phenotype (macular pigment optical den-
sity or MPOD). The present application will characterize how light distribution on the retina and MPOD affect 
melatonin suppression. We hypothesize that light incipient on the retina in central vision (i.e., at the fovea) 
will be more effective at suppressing melatonin than light reaching the periphery of the retina, and that 
melatonin suppression will be inversely correlated with MPOD. We further hypothesize that, compared to 
age-matched controls, mild cognitive impairment (MCI) patients will have lower MPOD than age-matched 
controls. Finally, we will explore the relationship between MPOD and cognition and the feasibility of using 
MPOD as a biomarker of individual light sensitivity. The following aims will be investigated: 
Specific aim 1: To determine how retinal light distribution impacts melatonin suppression in patients with 
MCI and in age-matched controls: We will investigate whether changing light distribution pattern from “on-
axis”’ (i.e., directed along the eye’s visual axis to the fovea) to “off-axis” (i.e., directed on the periphery of the 
eye’s visual axis) impact melatonin suppression. Given the retinal morphology and the highest density of pho-
toreceptors in the 2° field of view, we hypothesize that, for the same light level, light delivered on-axis will be 
more effective at suppressing melatonin than light delivered off-axis.  
Specific aim 2: To investigate how macular pigment optical density (MPOD) affects melatonin suppression 
in patients with MCI and in age-matched controls: The macula, an oval-shaped, yellow pigmented area lo-
cated at the center of the retina, preferentially filters out short-wavelength optical radiation with a peak ab-
sorbance around the same wavelength as the peak spectral sensitivity of the human circadian system (460 nm). 
1 We hypothesize that melatonin suppression will be inversely correlated with MPOD measurements.  
Specific aim 3: To investigate how MPOD is associated with cognition. Given that MPOD has been shown to be 
related to cognition (based on mini-mental state examination composite scores, visual-spatial and constructional abilities, 
language ability, attention, and the total scale on the Repeatable Battery for the Assessment of Neuropsychological Sta-
tus), 12 we also hypothesize that MCI patients will have lower MPOD scores and that MPOD measurements will be neg-
atively associated with cognition, as measured by the Montreal Cognitive Assessment (MoCA), Digital symbol substitu-
tion, Digital Span and Verbal Fluency. 
Findings from the proposed research project will provide feasibility and efficacy for future studies designed to 
test a more comprehensively tailored lighting intervention to promote circadian entrainment and improve 
sleep consolidation in persons with ADRD, who typically spend a significant amount of time indoors, with 

little daytime light exposure and perhaps too much nighttime light exposure. Currently, the tailored lighting 
intervention used in our previous studies only takes into account light's spectrum and amount and is not opti-
mized for light distribution in the retina. A secondary outcome will be a better understanding of how MPOD 
may be associated with cognitive decline. These results will help us develop light-based interventions de-
signed to deliver a robust light-dark pattern to MCI and ADRD patients, which will promote better sleep 
and better cognition. The proposed exploratory study is directly responsive to the goals of PA-18-347. 
RESEARCH STRATEGY 
Background 
Approximately 40% of the estimated 5.5 million older (65+) Americans with Alzheimer's disease and related 
dementias (ADRD) suffer from severe dysfunction of their sleep-wake and circadian systems, manifesting clin-
ically as sundowning, excessive daytime sleepiness, nocturnal wandering, agitation, and day-night reversal. 3,4 
Recent animal and human studies suggest a bi-directional relationship wherein circadian and sleep disruption can also 
influence AD onset and progression. An increase in amyloid plaque deposition has been reported due to chronic sleep dep-
rivation, with sleep extension protocols reporting lower plaques.  13,14 In people with mild cognitive impairment 
(MCI), an “at risk” or potential prodromal stage of dementia, sleep-wake disturbance is evident in up to 60% 
of patients. 5,6 Sleep is critical for healthy cognitive processing, including working and long-term memory, with 
specific neural events recorded from scalp electroencephalography (EEG) associated with memory enhance-
ment. Poor sleep and decreased memory-related sleep EEG events have been associated with decreased 
memory functioning in both groups. 15 Importantly, light treatment has been shown to improve sleep in older 
adults, and our group has preliminary evidence from a light treatment study in AD patients of improved 
sleep, mood, and behavior. The specification of lighting for these interventions has mainly been based on light's 
amount and spectrum, and has not taken retinal light distribution into account. One of the issues with this approach is 
the risk of glare and discomfort. A better understanding of the retinal sensitivity would allow for the development of de-
vices delivering more precise, and therefore, more effective doses. 
Sleep, circadian rhythms and light. The sleep/wake pattern is directly driven by the timing signals generated 
by the suprachiasmatic nuclei (SCN), which is known to be compromised by aging and ADRD. Studies have 
shown a reduced circadian rhythm amplitude after the age of 50.16,17 It is hypothesized that some of the neural 
processes involved in entrainment might become dysfunctional or less effective as we age.18 Disturbances in 
circadian rhythms leading to poor sleep in older adults can be the result of dysfunctional circadian pathways 
or a pathway that cannot process light information with as much fidelity. Also, the first stage of phototrans-
duction (when light signals are converted into neural signals) is negatively affected. Older adults not only 
have reduced optical transmission at short wavelengths, which is maximally effective for the circadian system, 
they also lead a more sedentary indoor lifestyle, with less access to bright light during the day. In fact, research 
demonstrates that middle-aged adults receive approximately 58 minutes of bright light per day19 while older 
adults in assisted-living facilities receive bright light for only 35 minutes per day.20 Finally, changes in the am-
plitude and timing of melatonin and core body temperature rhythms may occur in older adults. Lower ampli-
tude of melatonin rhythms may be associated with reduced sleep efficiency and deterioration of internal circa-
dian rhythms, such as hormone production, alertness, and performance.21,22,23 In order to maintain synchroni-
zation in the face of these physiological changes, it is necessary both to increase the strength of the light stimu-
lus and to design an intervention that is maximally effective for entraining the circadian systems of those with 
MCI and ADRD. A 24-h light-dark pattern incident on the retina is the most efficacious stimulus for entraining 
the circadian system in humans.24 Indeed, a carefully orchestrated light-dark pattern has been shown to be a 
powerful nonpharmacological tool to improve sleep efficiency and consolidation in several controlled studies 
of older populations, with and without ADRD.25-27 More recently, work from our own laboratory showed in-
creased sleep efficiency and reduced depression and agitation behavior after only 4 weeks of a tailored lighting 
intervention.28 However, current approaches to light therapy for reducing sleep disturbances as well as depressive and 
agitation symptoms in MCI and ADRD patients do not consider the non-uniform photoreceptors’ mosaic in the retina, 
and light therapy tends to be too bright and uncomfortable for users. This proposal will lay the foundation for the develop-
ment of more precise light treatment devices to effectively promote better sleep and quality of life in this population. 
Non-uniform photoreceptors’ mosaic across retina: The retina is a complex neural network lining the back of 
the eye, made up of numerous nerve cell bodies segmented into 3 distinct layers: ganglion cell layer (GCL) 

where the intrinsically photosensitive retina ganglion cells (ipRGCs) are located, the inner nuclear layer (INL) 
composed of the collector cells, and the outer nuclear layer (ONL) where the classical photoreceptors (rods and 
cones) are located. Our visual acuity (e.g., ability to read black text on white paper) is characterized by long (L) 
and middle (M) cone responses. The human circadian system, however, has a spectral sensitivity close to 460 
nm, which falls within the sensitivity range of the short (S) cones. Even though the ipRGCs are the principal 
conduit of neural signals from the retina to the SCN, 29,30 they also receive and integrate signals from the classi-
cal photoreceptors. 31,32 More importantly, each of these photoreceptor classes involved in circadian photo-
transduction has a distinct distribution as a function of retinal eccentricity, which creates a non-uniform photo-
receptors mosaic within the retina. Cumulatively, for most of the retina, rod photoreceptor density is substan-
tially higher compared to the cone photoreceptor density. 33-35 However, an inverse trend can be observed in 
the fovea, wherein the cone density increases almost 200-fold with a concomitant sharp decline in rod density. 
The distribution across the retina is also quite different for the 3 cone types. The L- and M-cones are densely 
packed in the fovea, with a sharp decline in their density with increasing retinal eccentricity. 33-35 The S-cone 
density, although reported to be low in the fovea, peaks in the parafoveal region, followed by a gradual de-
cline with a subsequent increase in retinal eccentricity. Thus, in theory, it is possible that different portions of the 
retina illuminated by same photic stimulus will yield circadian responses of varying magnitudes. 
Past studies looking at lighting distribution and circadian system’s response: Despite well-established re-
search on the topography of photoreceptors across the retina, there is a troubling dearth of research on the spa-
tial sensitivity of the human circadian system. No studies over the past 15 years have consistently and conclu-
sively determined how lighting distribution at the eye, and more importantly, on the retina, modulates the cir-
cadian efficacy of the incident dose. For example, an early study by Adler, et al. 36 treated 12 healthy subjects to 
bright light exposure (1000 lux) under 2 spatial lighting scenarios: central (5°) and laterally peripheral (60°), 
but failed to report a significant difference in melatonin suppression between the 2 lighting conditions. An an-
other study concluded that illuminating the entire retina is more effective for suppressing melatonin than illu-
minating (at equal photon dose) only the retina’s inferior portion. 37 Some studies found that illuminating the 
inferior portion of the retina was more effective for suppressing melatonin than the superior portion,12 a find-
ing that was not supported by a subsequent study.38 Taking a different approach, another study involving sub-
jects exposed to either a monocular or binocular light stimulus, found that exposure to a white light source 
(630 lx) induced significantly greater melatonin suppression when both eyes were stimulated compared to just 
one eye. 39,40 Despite these disparate findings, and the somewhat rudimentary methods for estimating the reti-
nal exposures used by the studies to date, it is nonetheless generally understood that the human circadian sys-
tem's ability to weigh  and integrate photic stimuli spatially, and subsequent regulation of melatonin synthesis, is bound 
to be affected by the physical orientation of a light source and the gaze behavior relative to the light source.  
Macular pigment optical density (MPOD): In addition to the photoreceptors, the density of the short-wave-
length optical radiation attenuating macular pigment has also been shown to vary across the retina. Typically, 
the concentration of the macular pigment is highest at, or near, the fovea and rapidly decreases with an in-
crease in eccentricity. In healthy adults, MPOD has been shown to vary by almost one log unit (0.1–1.0), and 
that the within population MPOD variance can be largely explained by factors such as diet, age, and genetics41. 
Therefore, MPOD may be used as a biomarker for individual sensitivity to light treatment. 
Relationship between macular carotenoids and cognitive function: The macular carotenoids lutein (L) and 
zeaxanthin (Z) preferentially accumulate in the central retina where their concentrations can be reliably as-
sessed by measuring MPOD. 42 L and Z carotenoids have been shown to breech the blood–brain barrier and 
accumulate in various diffuse brain regions, with an especially high correlation reported between retinal L and 
Z levels and those estimated in occipital brain areas. 43-46 In other words, a close relationship between the mac-
ular carotenoids (and the retina itself) and the rest of the central nervous system 47-50 has enabled the research-
ers to employ MPOD as a proxy for neural L and Z concentrations. 45 More importantly, a number of studies 
have shown that higher concentrations of L and Z, as measured by higher MPOD values, have been signifi-
cantly associated with improved cognitive performance, 47,51-57 potentially by strengthening neural structure 
and augmenting neural efficiency. 49 For example, a recent study has reported significantly lower performance 
on global measures of cognitive functioning (based on Mini-Mental Status Exam and Montreal Cognitive As-
sessment outcomes) in older adults with low MPOD values. 58 MPOD has also been associated with other cog-
nitive functions regulating attention, visual memory, learning, and cognitive flexibility measuring subject’s 

ability to switch tasks. 54 Taking a different approach, an exploratory clinical trial found that supplementing 
older females with L improved their verbal fluency and performance on memory tests. 59 More recently, a pla-
cebo-controlled trial involving older adults found that L and Z dietary supplements improved performance on 
measures of complex attention and cognitive flexibility. 52 Overall, an increase in MPOD by even about 0.09 log 
units through dietary supplementation has been shown to improve cognition. 57 In this feasibility study, we will 
investigate the exploratory hypothesis that MCI patients who have lower MPODs and lower cognition will be more sensi-
tive to light at night and suppress more melatonin when light is delivered on-axis, which will lead to circadian disruption. 
Significance and Innovation 
The proposed study will ‘shed light’ on a relatively 
unexplored avenue of circadian phototransduction 
and spatial sensitivity, an understanding of which 
is essential for specifying and implementing a 
lighting design in healthcare facilities, senior care 
living facilities, and residences of MCI and ADRD 
patients. Findings from the proposed research pro-
ject will be used to expand upon the Lighting Re-
search Center 's previous related work formulating 
an extensive mathematical model of human circa-
dian phototransduction (“CS model”) 60 based on the effects of retinal light exposures on nocturnal melatonin 
suppression, which is consistent with the neuroanatomy and physiology of the human retina. The model has 
been extensively used in the laboratory and the field to predict efficacy of light exposures on clinically relevant 
outcome measures, such as sleep onset time, demonstrating its scientific and face validity. The model does not, 
however, take into account human retinal sensitivity resulting from non-uniform photoreceptor distribution. 
The results of the proposed research would inform the development of light-delivery methods to promote 
circadian entrainment and improve sleep consolidation in patients afflicted with MCI and ADRD, who typ-
ically spend a significant amount of time indoors. Several studies in the literature have associated AD with 
an increase in circadian disruption. 61,62 Prior work by Dr. Figueiro (PI) has shown that appropriately timed 
light exposure can increase sleep efficiency (Fig. 1), decrease agitation, and even limit cognitive decline in the 
ADRD population, 63 but the light delivery method and strategy has been identified as one of the greatest chal-
lenges for successful treatment. Results from the proposed research are also important to this specific applica-
tion, as past studies have reported significantly lower MPODs in MCI and ADRD populations. 64 Finally, we 
will be able to better understand whether MPOD affects cognition and explore the possibility that MPOD 
could be used as a biomarker for individual sensitivity to light, allowing for the development of individualized 
light treatment prescriptions to more effectively entrain the circadian system, thus, improving sleep and cogni-
tion.  
Following advancements in LED technology that allow more dynamic distribution patterns for light sources, 
the proposed work marks an important shift in approach moving beyond the conventional “light at the cor-
nea” for circadian lighting to “light at the retina.” The meticulously planned study will test a novel strategy of 
whether modulating lighting distribution at the eye provides a more efficient way to manipulate circadian 
stimulus delivered, compared to amount or spectral modifications for light sources, which often are governed 
by requirements to satisfactorily perform visual tasks. The state-of-the-art custom-built lighting apparatus will 
allow us to selectively involve and study interaction of MPOD with the varying lighting characteristics (spec-
trum, distribution), which is unique as no prior studies have examined the correlation between MPOD and 
melatonin suppression. Lastly, the target spectra for the narrowband sources have been selected so that photic 
stimulus incident on the retina will be attenuated by the macular pigment (peak absorbance = 460 nm) only for 
the blue light and not the green light exposures proposed for the study (see Experimental Conditions). 
Approach  
Study Team: Study Team: Mariana Figueiro, PhD, Professor of Architecture and Biological Sciences at RPI 
and Director of the Lighting Research Center, specializes in human circadian responses to light. She is 
currently a PI on an R01 investigating the impact of light on sleep efficiency of older adults with ADRD living 
in nursing homes. She is also a PI on another R01 investigating the impact of a tailored lighting intervention 
Fig. 1. Tailored lighting intervention (TLI) during a 6-month randomized 
single-arm design clinical trial involving 47 persons with ADRD living in 
long-term care facilities improved measures of sleep. The error bars repre-
sent standard error of the mean. *** p<0.001, ** p<0.01 and * p<0.05 

technology  on metabolic syndrome in ADRD and MCI patients. Rohan Nagare, PhD, is a research scientist 
with expertise in circadian phototransduction mechanisms and modeling. Mark Rea, PhD, Professor of 
Cognitive Sciences and Architecture at RPI, has been actively involved in modeling human visual response to 
light, and his accomplishments include the development of the first model of human circadian photo-
transduction. Barbara Plitnick, RN, is the Manager of Light and Health Program who has over 15 years of 
experience recruiting and running studies for a series of light and health projects. 
Preliminary Data:  
Role of MPOD in circadian photoreception: Nagare et al. 
have recently conducted a series of within-subjects nighttime 
studies recording light-induced melatonin suppression in hu-
man subjects exposed for 1 h to white light sources with CCTs 
ranging from 3300 K to 5000 K. Measurements for MPOD 
were performed using a non-invasive instrument employing 
psychophysical optical technique based on heterochromatic 
flicker photometry to determine MPOD’s role in circadian 
photoreception. It was observed that a higher MPOD was sig-
nificantly correlated with lower melatonin suppression, 
wherein the macular pigment acted as a filter, lowering the 
absolute circadian sensitivity (Fig. 2). The effect size of this 
observation further indicated that about 35% of the light in-
cident on cornea was being modulated by the macular pig-
ment for the rectangular light sources used in the study. 
These studies were performed using healthy young adults and our 
proposal will extend these results to include older adults, including those with MCI, who have been shown to be less sen-
sitive to light overall. Moreover, preliminary data from our lab using a protocol similar to the one described here (results 
described in introduction) showed that light delivered on axis is almost twice as effective as light delivered off axis. There-
fore, in order to deliver a robust light-dark pattern to promote entrainment and minimize nighttime melatonin 
suppression, a better understanding of the retinal mechanisms associated with circadian phototransduction is 
needed.  
Participant selection: Following IRB approval, we will recruit 24 MCI participants and 24 healthy, age-matched 
controls through e-mail notices, posters, and word-of-mouth. MPOD will be assessed at the recruitment stage 
for all subjects to determine their initial eligibility, which will require subjects to fit into one of 2 distinct 
groups (low: MPOD < 0.3, high: MPOD > 0.5). Eligible participants will be MCI or mild AD patients who are 
55 years and older. We will work with our physician collaborators in the area (who are currently working with 
the PIs in 3 other R01s) to perform the pre-selection diagnosis according to the following pre-selection criteria: 
Participants must be diagnosed by their physician with amnestic MCI or mild AD. Subjects in the control 
group will have normal cognition. Study participants who meet the following inclusion and exclusion will dis-
cuss informed consent for study participation: Inclusion criteria: Those taking antidepressants will be in-
cluded, but type of medicine and dosage intake will be monitored. There will be no exclusions based gender, 
race, and ethnicity. Participants must also not meet the following Exclusion criteria: Presence of another brain 
disease that fully explains the dementia (extensive brain vascular 
disease, Parkinson’s disease, dementia with Lewy bodies, traumatic 
brain injury, or multiple sclerosis); residence in a skilled nursing fa-
cility or long-term care; indication for psychiatric hospitalization or 
acute suicidality in the opinion of the physician; major organ failure 
(e.g., kidney failure); or uncontrolled generalized disorders such as 
hypertension or diabetes. Exclusion criteria will also extend to ob-
structing cataracts, macular degeneration, and blindness. Those tak-
ing over-the-counter melatonin, prescription sleep medication or beta 
blockers will be excluded. We will review the participants’ ophthal-
mologic tests during selection and exclude those who have undergone 
Fig. 3. Relative spectral power distributions 
of potential narrowband blue light source 
(λmax = 451 nm) and green light source (λmax 
= 522 nm). Also shown is the relative spectral 
absorbance of the macular pigment, adapted 
Fig. 2. Correlation between MPOD and melatonin 
suppression showing pooled data from a series of 
within-subjects nighttime studies. Each yellow dia-
mond corresponds to suppression data for an individ-
ual subject. The black line corresponds to the best fit 
linear regression model. All subjects underwent  a 1-h 
exposure  to white light sources with CCTs ranging 

cataract surgery and received an intraocular lens coated with ultraviolet- and blue-blocking filters (400-
440/440-500 nm). Those with a history of severe photosensitivity dermatitis, severe progressive retinal disease 
(e.g., macular degeneration), or a permanently dilated pupil (e.g., after certain types of cataract surgery) will 
also be excluded. Subjects will also be required to maintain a regular sleep schedule (bedtimes no later than 
23:00 and wake times no later than 08:00) starting 2 weeks prior to the experimental sessions and continuing 
throughout the experiment’s duration. The experimenters will run the dim-light control condition first, and 
any subjects who present low nighttime (i.e., at 24:00) melatonin levels will be excluded from the study. This 
study will conform to the Code of Federal Regulations (CFR) document Protection of Human Subjects, 45 CFR 
46, 67 and International Ethical Standards. 68  
Experimental conditions: In addition to a dim-light control condition, participants will be exposed to 2 narrow-
band sources: blue light (λmax = 451 nm) and green light (λmax = 522 nm) (Fig. 3), presented in 4 interventions. 
The 2 interventions for each narrowband source, designated on-axis and off-axis, will have distinct lighting 
distribution patterns but calibrated to deliver the same targeted levels of circadian light (CLA) and circadian 
stimulus (CS) at the eye. 60,69 The 4 interventions will target a CS = 0.40 (≈ 27 lux for blue light, ≈ 250 lux for 
green light) at the participants’ eyes and the dim light control will target a CS < 0.1 (< 5 lux of 2700 K light) at 
the eyes. The 4 lighting conditions will be counter-balanced across all the participants. Over the course of the 
study, spectral irradiance measurements for the 2 narrowband sources will be performed using a spectrometer 
(Model USB650, Ocean Optics, Winter Park, FL, USA).  
Lighting apparatus: The on-axis and off-axis lighting interventions will be delivered via RGB color-tunable 
LED luminaires (model G2, Ketra, Austin, TX), each driven by a satellite link controller (model N3, Ketra) with 
a touchpad interface (model X1, Ketra) and housed in fixtures that will be placed directly on desks at which 
the participants will be seated. The luminaires will be covered by spectrally neutral diffusers to eliminate po-
tential glare. The intervention stimulus will be calibrated using a tripod-mounted illuminance meter (Model X-
91, Gigahertz-Optik, Haverhill Rd, Amesbury, MA, USA). The target photometric characteristics of the inter-
vention light stimulus for measures of illuminance, CLA, and CS following Rea and Figueiro 70, and equivalent 
melanopic lux (EML) following Enezi, et al. 71 are shown in Table 1. To ensure consistency of the delivered 
lighting dose, participants will be required to use a chin rest, optimally adjusted to maintain a fixed distance of 
30 in. from the 22 in. x 5 in. (w × h) light-emitting area of the desktop luminaire (Fig. 4). The on-axis interven-
tion will provide an image ± 5° in width at each participant’s eyes. The off-axis intervention will provide an 
image ± 8–20° in width at each participant’s eyes.  
Table 1. Photometric characteristics of the target blue light and green light stimulus calculated following Rea and Figueiro 
70 (CS) and Enezi, et al. 71 (EML) 
Experimental condition 
Photopic illuminance (lux) 
CLA 
EML 
Predicted CS 
Blue on-axis /Blue off-axis 
26.7 
473.7 
154.0 
0.40 
Green on-axis /Green off-axis 
250.0 
473.7 
274.0 
0.40 
Participant measurements and field monitoring procedures: 
Macular pigment optical density (MPOD): Measurements for MPOD will be performed using a non-invasive 
instrument (QuantifEye MPS II, ZeaVision (LLC), Chesterfield, MO) employing well-established psychophysical 
optical technique based on heterochromatic flicker photometry. 72 Pupil measurement: Participants’ pupil diame-
ters will be estimated while they are exposed to all interventions using a digital video camcorder (model DCR-TRV140, 
SONY Electronics, Minato, Tokyo, Japan) and subsequent frame-wise analyses using an open-source web application (Pixel 
Fig. 4. The layout of the desktop luminaires with 
respect to the participants’ eyes during the exper-
iment (left), and the luminaires’ configuration 
when delivering the on-axis and off-axis inter-
ventions (right). The circle shown in the center of 
the luminaires represents a low-power LED that 
will be used as a simple on-axis visual task to 
maintain participants line of sight. 

Ruler, MIOPlanet Technologies, Rimouski, PQ, Canada) that estimates pupil diameter for 5 samples per 15-s video seg-
ment. We will then calculate the retinal illuminance. The simplified formula is T = LS, where L is the lumi-
nance of the stimulus cd/m2 and S is the area of the pupil in mm2. The retinal illuminance T is given in trolands. 
Sleep/wake diary: Subjects will maintain a sleep/wake diary during the entire study. These diaries will docu-
ment bedtimes, rising times, and caffeine intake. Actigraphy: The actigraph is a device the size of a digital wrist 
watch (1.75” x 1.3” x 0.38”, weighing 2 oz) that is worn on the nondominant wrist (Actiwatch, Philips Respi-
ronics, Murrysville, PA, or similar). Subjects will begin to wear the device 7 days prior to starting the protocol 
and throughout the duration of the data collection period. When subjects return to the laboratory for the exper-
imental sessions, the actigraph data will be downloaded and compared to the diary information. Discrepancies 
will be identified and the actigraph record will be annotated. The data will be analyzed to estimate sleep/wake 
using the manufacturer’s software. Cognitive tests: In addition to MOCA (described above), participants will be asked 
to perform the following tests at recruitment: Digit Symbol Substitution (DSST): The DSST requires response speed, 
sustained attention, and set shifting (executive function). The participant is given 90 seconds to pair correctly numbers 
with symbols; the higher the score the better the performance. Digit Span: Measures working memory’s number storage 
capacity. The participant hears a sequence of numerical digits and is tasked to recall the sequence correctly. Digit span is 
the longest number of sequential digits that can be accurately remembered. Verbal Fluency: Participants have to produce 
as many words as possible starting with a given letter under various rule constraints. Successful retrieval requires executive 
control over cognitive processes such as selective attention and inhibition, mental set shifting, internal response generation 
and self-monitoring. 
Melatonin Suppression Protocol: On each study night, participants will be required to arrive at the laboratory 
at 23:30 and remain in dim light (< 5 lux at the eye) for 30 min, followed by a 60-min exposure to one of the 4 
experimental conditions (Fig. 5). To ensure consistency of the light distribution with regard to the participants’ 
line of sight over the course of the 1-h exposure, all participants will perform a simple on-axis visual task that 
involves responding (using a hand-held tally counter) to a flashing, pre-programmed RGB LED source (ge-
neric low-power) suspended in the center of the desktop luminaire (see Fig. 4). The visual task will not be per-
formed on the dim-light control night, when participants will be free to operate their personal electronic de-
vices (i.e., iPads, tablets, cell phones, etc.). However, all displays will be covered with orange-tinted media 
(Roscolux #21 golden amber, Rosco Laboratories, Stamford, CT, USA) to filter out radiation < 525 nm to pre-
vent participants from receiving circadian-effective light from their self-luminous devices. In a previous study, 
photometric measurements of the stimulus emitted by similarly filtered electronic displays revealed light lev-
els of < 5 lux, which translated to a CS of < 0.001 73.  
Over the course of each experimental session, 3 saliva samples (S1, S2, S3) will be collected from each partici-
pant for melatonin analysis. Saliva samples (1 ml) will be collected using the Salivette system (Sarstedt, 
Nümbrecht, DE), wherein the participant chews on a plain cotton cylinder for 1-2 min, which is immediately 
placed in a test tube, centrifuged for 5 min at 1000 g, and frozen (-20 º C). The frozen samples from each session 
will be assayed in a single batch using melatonin radioimmunoassay kits (Direct Melatonin RIA, ALPCO, Sa-
lem, NH, USA).  
Sample Size and Estimated Power. The study will have enough power to detect treatment differences. Previ-
ous work by our lab74 provides measures of variability for our primary outcome measures (melatonin suppres-
sion and questionnaires). In particular, a prior within subjects’ study74 involving effects of white light on 
nighttime melatonin suppression have shown that a sample size of 12 or more participants is enough to detect 
statistically significant (alpha = 0.05) difference in suppression (≈ 14%) for a large effect (Cohen’s d > 0.5) at a 
statistical power ≈ 95%. A sample size of 19 subjects (24 subjects, 20% attrition) for each group, therefore, 
should be sufficient for the detection of significant differences in melatonin suppression. 
Data and Statistical Analyses  
Fig. 5. Experimental protocol showing the relationship be-
tween on-axis and off-axis conditions, and salivary melatonin 
sample times (S1 [0 min], S2 [30 min], and S3 [60 min]).  

Anticipated Outcomes. Our hypothesis is that greater melatonin suppression will be observed for the on-axis 
interventions, compared to the off-axis interventions, due to 2 reasons: (1) the greater density of cone photore-
ceptors in central retina (which will account for about 12% melatonin suppression difference according to CS 
model calculations 70) and (2) the Stiles-Crawford effect, which suggests that the most effective optical rays inci-
dent on the retina are along the foveal axis. Overall, we also expect to see greater melatonin suppression for 
the low MPOD group compared to the high MPOD group, as higher MPOD means greater attenuation of the 
photic stimulus. We further hypothesize a significant interaction between the effect of MPOD and light source 
spectrum, as the yellow macular pigment preferentially filters out short-wavelength radiation, and hence 
should only attenuate the blue light stimulus. In other words, for high MPOD subjects, we expect to see greater 
melatonin suppression following exposure to the green light as compared to the blue light exposure. Lastly, 
we expect to observe a significant interaction between the effect of MPOD and lighting distribution, as since 
the yellow macular pigment is located primarily in the central retina, the off-axis should dose should not be 
affected by it. Finally, we hypothesize that lower MPOD scores will be associated with lower cognition.  
Overall Analyses will include (1) evaluation to determine data quality, (2) creation of constructed variables 
and determination of variable distributions, (3) applying tests of parametric statistical assumptions wherever 
appropriate, (4) preliminary (generally bivariate) testing of hypotheses, (5) consideration of potential covari-
ates to build into the statistical models to increase the probability of detecting treatment effects if they exist, 
and (6) development and elaboration of multivariate models. SPSS software (V25, IBM, Armonk, NY, USA) 
will be used for all statistical analyses (significance, p <0.05). Dr. Nagare will perform all statistical analyses 
and work with Drs. Figueiro and Rea on statistical analyses.  
Aims 1, 2: In order to evaluate outcomes of the intervention, we will first determine the melatonin suppression 
for each condition by comparing melatonin levels collected during the dim-light control week to those at the 
same time in the experimental conditions’ weeks. We will then perform a mixed-model analysis of variance 
(ANOVA), with lighting distribution (on-axis vs. off-axis) and spectrum (blue light vs. green light) serving as 
the within-subjects factors, and MPOD group (high MPOD > 0.5 vs. low MPOD < 0.3) and cognitive status 
(MOCA scores) (healthy vs. MCI participants) serving as the between-subjects factors. Mixed model analyses 
allow for different numbers of observations for different subjects (e.g. if there are dropouts). As sample size 
and its associated degrees of freedom allow, we will also adjust for covariates that may be associated with out-
come measures, such as retinal illuminance, gender, season and any medication load. Within the limits of the 
sample, we will explore treatment-covariate interactions for each participant-level covariate. If strong interac-
tions are observed, it will suggest that a future study could possibly be stratified on the given factor. To further 
assess the impact of MPOD on individual light sensitivity, a Pearson correlation coefficient will be calculated 
between melatonin suppression and MPOD values recorded across MCI patients and healthy older adults. We 
hypothesize a negative correlation, wherein higher MPOD values will be associated with lower suppression. 
Aim 3: To investigate an association between MPOD and cognition, a Pearson correlation coefficient will also 
be calculated between MPOD and MoCA scores and the cognitive tests scores. We hypothesize a positive cor-
relation, wherein lower MPOD values will be associated with lower cognition. 
Potential pitfalls and Alternate Approaches . Experiment validity will be assessed by observing the expected 
main effect of light exposure duration, wherein we should be recording greater melatonin suppression follow-
ing 60-min exposure as compared to the 30-min exposure. In case, the experiment results fail to report signifi-
cant main effects due to chromatic adaptation to the narrowband light exposures, as an alternative approach, 
the study would be re-run using polychromatic white light sources, at the expense of not examining the spec-
trum effect.  
Timeline: Detailed in human subjects’ section. 
 

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