Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology

Morgia, Chiara La; Carelli, Valerio; Carbonelli, Michele

doi:10.3389/fneur.2018.01047

Cited by 50 publications

(50 citation statements)

References 81 publications

(111 reference statements)

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“…Interest on the in vivo evaluation of mRGC function as a potential biomarker for different pathological conditions is growing. Melanopsin is a photopigment contained in mRGCs that selectively reacts to short-wavelength blue light (459–483 nm) [8, 9, 19, 20]. The immediate and apparent reaction to mRCGs depolarization in response to light is a pupillary constriction that can be assessed by chromatic pupillometry [8, 9, 19, 20].…”

Section: Introductionmentioning

confidence: 99%

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer’s disease

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Sultan

et al. 2019

PLoS ONE

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BackgroundMelanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body’s circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer’s disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD.MethodsWe performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid β42 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid β42 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm.ResultsOur results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls.ConclusionsThe variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD.

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Section: Introductionmentioning

confidence: 99%

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer’s disease

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Sultan

et al. 2019

PLoS ONE

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“…These findings support that sleep-wake history control, or at least monitoring, should be implemented in all protocols considering tonic or steady-state pupil size, and baseline correction should be included in studies or clinical examination focused on phasic pupil responses (e.g., to light exposure). The findings have indeed implications for clinical practice where pupil measures, including PLR and PIPR, may aid diagnosis or follow-up in eye or brain diseases, like glaucoma, multiple sclerosis, Seasonal Affective Disorders or Parkinson's disease [81]. Finally, our study suggest that sustained-attention performance, fatigue, and affective states may be monitored via pupil measures, but does not support that they constitute reliable markers of subjective sleepiness and objective EEG measures of alertness, at least in healthy young men, and in the conditions inherent to the present experiment.…”

Section: Discussionmentioning

confidence: 95%

Steady-State Pupil Size Varies with Circadian Phase and Sleep Homeostasis in Healthy Young Men

et al. 2019

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Pupil size informs about sympathovagal balance as well as cognitive and affective processes, and perception. It is also directly linked to phasic activity of the brainstem locus coeruleus, so that pupil measures have gained recent attention. Steady-state pupil size and its variability have been directly linked to sleep homeostasis and circadian phase, but results have been inconsistent. Here, we report robust changes in steady-state pupil size during 29 h of continuous wakefulness in healthy young men (N = 20; 18–30 years old) maintained in dim-light in strictly controlled constant routine conditions. These variations were associated with variations in motivation and sustained attention performance. Pupil size variability did not significantly change during the protocol. Yet, pupil size variability was linearly associated with subjective fatigue, sociability, and anguish. No associations were found between neither steady-state pupil size nor pupil size variability, and objective EEG measure of alertness and subjective sleepiness. Our data support therefore the notion that, compared with its variability, steady-state pupil size is strongly influenced by the concomitant changes in sleep need and circadian phase. In addition, steady-state pupil size appears to be related to motivation and attention, while its variability may be related to separate affective dimensions and subjective fatigue.

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“…The function of mRGCs is, however, difficult to explore in vivo, since these cells represent a small subgroup (about 1%) of the regular RGCs, and also mRGCs receive some input from rods and cones (Hannibal et al, 2017). Chromatic pupillometry protocols have been developed to isolate the contribution of mRGCs to the PLR and to assess in vivo the function of mRGCs (Kardon et al, 2011;Park et al, 2011;La Morgia et al, 2018). These protocols are based on light stimuli at different wavelengths and with light adaptation conditions aimed at isolating the contribution of single photoreceptors, taking into account that mRGCs are maximally sensitive to blue light at 480 nm (Berson et al, 2002).…”

Section: Neurodegenerativementioning

confidence: 99%

Chromatic Pupillometry Findings in Alzheimer’s Disease

et al. 2020

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Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for nonimage forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mildmoderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

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Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology

Cited by 50 publications

References 81 publications

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer’s disease

Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer’s disease

Steady-State Pupil Size Varies with Circadian Phase and Sleep Homeostasis in Healthy Young Men

Chromatic Pupillometry Findings in Alzheimer’s Disease

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