The impact of Alzheimer's disease (AD) on the pupillary light response (PLR) is controversial, being dependent on the stage of the disease and on the experimental pupillometric protocols. The main hypothesis driving pupillometry research in AD is based on the concept that the AD-related neurodegeneration affects both the parasympathetic and the sympathetic arms of the PLR (cholinergic and noradrenergic theory), combined with additional alterations of the afferent limb, involving the melanopsin expressing retinal ganglion cells (mRGCs), subserving the PLR. Only a few studies have evaluated the value of pupillometry as a potential biomarker in AD, providing various results compatible with parasympathetic dysfunction, displaying increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum velocity of constriction (MCV) and maximum constriction acceleration (MCA) compared to controls. Decreased MCV and MCA appeared to be the most accurate of all PLR parameters allowing differentiation between AD and healthy controls while increased post-illumination pupillary response was the most consistent feature, however, these results could not be replicated by more recent studies, focusing on early and pre-clinical stages of the disease. Whether static or dynamic pupillometry yields useful biomarkers for AD screening or diagnosis remains unclear. In this review, we synopsize the current knowledge on pupillometric features in AD and other neurodegenerative diseases, and discuss potential roles of pupillometry in AD detection, diagnosis and monitoring, alone or in combination with additional biomarkers.

Objective To evaluate the performance of a deep learning system (DLS) in classifying the severity of papilledema associated with increased intracranial pressure on standard retinal fundus photographs. Methods A DLS was trained to automatically classify papilledema severity in 965 patients (2,103 mydriatic fundus photographs), representing a multiethnic cohort of patients with confirmed elevated intracranial pressure. Training was performed on 1,052 photographs with mild/moderate papilledema (MP) and 1,051 photographs with severe papilledema (SP) classified by a panel of experts. The performance of the DLS and that of 3 independent neuro-ophthalmologists were tested in 111 patients (214 photographs, 92 with MP and 122 with SP) by calculating the area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, and specificity. Kappa agreement scores between the DLS and each of the 3 graders and among the 3 graders were calculated. Results The DLS successfully discriminated between photographs of MP and SP, with an AUC of 0.93 (95% confidence interval [CI] 0.89–0.96) and an accuracy, sensitivity, and specificity of 87.9%, 91.8%, and 86.2%, respectively. This performance was comparable with that of the 3 neuro-ophthalmologists (84.1%, 91.8%, and 73.9%, p = 0.19, p = 1, p = 0.09, respectively). Misclassification by the DLS was mainly observed for moderate papilledema (Frisén grade 3). Agreement scores between the DLS and the neuro-ophthalmologists’ evaluation was 0.62 (95% CI 0.57–0.68), whereas the intergrader agreement among the 3 neuro-ophthalmologists was 0.54 (95% CI 0.47–0.62). Conclusions Our DLS accurately classified the severity of papilledema on an independent set of mydriatic fundus photographs, achieving a comparable performance with that of independent neuro-ophthalmologists. Classification of Evidence This study provides Class II evidence that a DLS using mydriatic retinal fundus photographs accurately classified the severity of papilledema associated in patients with a diagnosis of increased intracranial pressure.

To evaluate the ability of chromatic pupillometry to reveal abnormal pupillary responses to light in patients with early-stage primary open-angle glaucoma (POAG) and to test whether the degree of pupillometric impairment correlates with structural hallmarks of optic nerve damage in the disease. Cross-sectional study. Forty-six patients with early-stage POAG (63.4±8.3 years, 63% male, 87% ethnic-Chinese) and 90 age-matched healthy controls (61.4±8.6 years, 34% male, 89% ethnic-Chinese). Patients with POAG had a visual field mean deviation (VFMD) of -6 decibels or better on automated perimetry. Each participant underwent a monocular 2-minute exposure to blue light (462 nm) followed by another 2-minute exposure to red light (638 nm) using a modified Ganzfeld dome equipped with a light-emitting diode lighting system. The light stimuli intensity was increased logarithmically to evaluate the combined extrinsic and intrinsic response of intrinsically photosensitive retinal ganglion cells (ipRGCs). Light-induced changes in horizontal pupil diameter were assessed monocularly using infrared pupillography. Baseline-adjusted, light-induced pupillary constriction amplitudes were calculated, and individual irradiance-response curves were constructed for each stimulus. Pupillary constriction amplitudes were compared between groups and across light intensities using a linear mixed model analysis. The linear relationship between pupillometric parameters and different structural and functional features of glaucoma was assessed using Pearson's correlation analysis. Light-induced pupillary constriction was reduced in patients with early-stage POAG compared with controls at moderate to high irradiances (≥11 Log photons/cm2/s) of blue (P = 0.003) and red (P < 0.001) light. Maximal pupillary constriction amplitude was correlated with retinal nerve fiber layer thickness (RNFL) thickness (blue: r = 0.51, P < 0.001; red: r = 0.45, P = 0.002) in patients with POAG but not in controls. Conversely, pupillometric parameters were not correlated with visual field scores in patients with early-stage POAG. Patients with early-stage POAG exhibit reduced pupillary responses to moderate and high irradiances of blue and red lights. This wavelength-independent functional alteration correlates with structural thinning of the RNFL and could be the consequence of dysfunction or loss of melanopsin expressing ipRGCs in the early stages of the disease.

Glaucoma is an age related disease characterized by the progressive loss of retinal ganglion cells, which are the neurons that transduce the visual information from the retina to the brain. It is the leading cause of irreversible blindness worldwide. To gain further insights into primary open-angle glaucoma (POAG) pathophysiology, we performed a non-targeted metabolomics analysis on the plasma from POAG patients (n = 34) and age- and sex-matched controls (n = 30). We investigated the differential signature of POAG plasma compared to controls, using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). A data mining strategy, combining a filtering method with threshold criterion, a wrapper method with iterative selection, and an embedded method with penalization constraint, was used. These strategies are most often used separately in metabolomics studies, with each of them having their own limitations. We opted for a synergistic approach as a mean to unravel the most relevant metabolomics signature. We identified a set of nine metabolites, namely: nicotinamide, hypoxanthine, xanthine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline with decreased concentrations and N-acetyl-L-Leucine, arginine, RAC-glycerol 1-myristate, 1-oleoyl-RAC-glycerol, cystathionine with increased concentrations in POAG; the modification of nicotinamide, N-acetyl-L-Leucine, and arginine concentrations being the most discriminant. Our findings open up therapeutic perspectives for the diagnosis and treatment of POAG.