Dataset Information

Chromatic Pupillometry Findings in Alzheimer's Disease.

ABSTRACT: Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image 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 mild-moderate 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.

SUBMITTER: Romagnoli M

PROVIDER: S-EPMC7431959 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Chromatic Pupillometry Findings in Alzheimer's Disease.

Romagnoli Martina M Stanzani Maserati Michelangelo M De Matteis Maddalena M Capellari Sabina S Carbonelli Michele M Amore Giulia G Cantalupo Gaetano G Zenesini Corrado C Liguori Rocco R Sadun Alfredo A AA Carelli Valerio V Park Jason C JC La Morgia Chiara C

Frontiers in neuroscience 20200811

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image 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. W ...[more]

PMID: 32848556

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Project description:PurposeNovel therapeutic options, such as regenerative medicine and gene therapy, are now emerging as viable treatment options for patients with severe visual impairments, such as retinitis pigmentosa (RP). Gradable assessment of patients' visual function is essential to consider treatment options and to evaluate treatment outcomes; however, evaluation of visual function in patients with advanced low vision is often challenging because of patients' poor and sometimes unpredictable responses. In this study, we attempted to accurately assess visual capabilities and disease stage in patients with RP with a visual acuity (VA) of ≤ 0.01.DesignRetrospective analysis of visual function indicators, including VA, retinal thickness, full-field stimulus testing (FST), and chromatic pupillometry.SubjectsOverall, 43 patients (84 eyes) with advanced RP with a VA of ≤ 0.01 visited Kobe City Eye Hospital from 2019 to 2021.MethodsHierarchical (multilevel) Bayesian modeling was used to estimate individual eye's pupil response and FST threshold, taking into account the ambiguity and randomness often observed in patients with ultralow vision. Using the estimated ability obtained from each test, the correlation between each test and retinal thickness was further analyzed to make a comprehensive assessment of the data.Main outcome measuresVisual acuity, retinal thickness, FST threshold, and pupil diameter change to different light stimuli.ResultsFull-field stimulus testing and pupillometry measurements were moderately correlated with VA but exhibited a wide range of values within the same VA groups. Full-field stimulus testing was not correlated with central retinal thickness at counting fingers/hand motion VA range and seemed to reflect overall remaining photoreceptor function, including peripheral retina. Pupillometry may be able to distinguish between different levels of inner retinal function.ConclusionsThe combination of pupillometry and FST allowed for graded evaluation of visual function within patients grouped in the same VA groups in patients with advanced RP with ultralow vision.Financial disclosuresProprietary or commercial disclosure may be found after the references.

Project description:Currently there are no reliable biomarkers for early detection of Alzheimer's disease (AD) at the preclinical stage. This study assessed the pupil light reflex (PLR) for focal red and blue light stimuli in central and peripheral retina in 125 cognitively normal middle age subjects (45-71 years old) at high risk for AD due to a family history of the disease (FH+), and 61 age-similar subjects with no family history of AD (FH-) using Chromatic Pupilloperimetry coupled with Machine Learning (ML). All subjects had normal ophthalmic assessment, and normal retinal and optic nerve thickness by optical coherence tomography. No significant differences were observed between groups in cognitive function and volumetric brain MRI. Chromatic pupilloperimetry-based ML models were highly discriminative in differentiating subjects with and without AD family history, using transient PLR for focal red (primarily cone-mediated), and dim blue (primarily rod-mediated) light stimuli. Features associated with transient pupil response latency (PRL) achieved Area Under the Curve Receiver Operating Characteristic (AUC-ROC) of 0.90 ± 0.051 (left-eye) and 0.87 ± 0.048 (right-eye). Parameters associated with the contraction arm of the rod and cone-mediated PLR were more discriminative compared to parameters associated with the relaxation arm and melanopsin-mediated PLR. Significantly shorter PRL for dim blue light was measured in the FH+ group in two test targets in the temporal visual field in right eye that had highest relative weight in the ML algorithm (mean ± standard error, SE 0.449 s ± 0.007 s vs. 0.478 s ± 0.010 s, p = 0.038). Taken together our study suggests that subtle focal changes in pupil contraction latency may be detected in subjects at high risk to develop AD, decades before the onset of AD clinical symptoms. The dendrites of melanopsin containing retinal ganglion cells may be affected very early at the preclinical stages of AD.

Project description:BACKGROUND:Melanopsin-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. METHODS:We 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. RESULTS:Our 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. CONCLUSIONS:The 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.

Dataset Information

Chromatic Pupillometry Findings in Alzheimer's Disease.

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Chromatic Pupillometry Findings in Alzheimer's Disease.

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