Retinal imaging in Alzheimer's and neurodegenerative diseases.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.

Predicting Thioflavin Fluorescence of Retinal Amyloid Deposits Associated With Alzheimer's Disease from Their Polarimetric Properties.

Purpose: To use machine learning in those with brain amyloid to predict thioflavin fluorescence (indicative of amyloid) of retinal deposits from their interactions with polarized light. Methods: We imaged 933 retinal deposits in 28 subjects with post mortem evidence of brain amyloid using thioflavin fluorescence and polarization sensitive microscopy. Means and standard deviations of 14 polarimetric properties were input to machine learning algorithms. Two oversampling strategies were applied to overcome data imbalance. Three machine learning algorithms: linear discriminant analysis, supporting vector machine, and random forest (RF) were trained to predict thioflavin positive deposits. For each method; accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve were computed. Results: For the polarimetric positive deposits, using 1 oversampling method, RF had the highest area under the receiver operating characteristic curve (0.986), which was not different from that with the second oversampling method. RF had 95% accuracy, 94% sensitivity, and 97% specificity. After including deposits with no polarimetric signals, polarimetry correctly predicted 93% of thioflavin positive deposits. Linear retardance and linear anisotropy were the dominant polarimetric properties in RF with 1 oversampling method, and no polarimetric properties were dominant in the second method. Conclusions: Thioflavin positivity of retinal amyloid deposits can be predicted from their images in polarized light. Polarimetry is a promising dye-free method of detecting amyloid deposits in ex vivo retinal tissue. Further testing is required for translation to live eye imaging. Translational Relevance: This dye-free method distinguishes retinal amyloid deposits, a promising biomarker of Alzheimer's disease, in human retinas imaged with polarimetry.

Does peripheral retinal input explain the promising myopia control effects of corneal reshaping therapy (CRT or ortho-K) & multifocal soft contact lenses?

In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors.

Diurnal rhythms of spherical refractive error, optical axial length, and power in the chick.

PURPOSE: To measure the diurnal variation of spherical equivalent refractive error (mean ocular refraction or MOR) and to investigate factors contributing to it in chick, an important animal myopia model. METHODS: Nine chicks developed naturally on a 14-hour light/10-hour dark cycle. Optical axial length (OAL) and Hartmann-Shack wavefront error (HSWE) measurements, including pupil size, were taken starting on day 7, at eight times during the following 32 hours. MOR was calculated for a constant pupil size from HSWE measurements. RESULTS: MOR, OAL, and pupil size showed significant diurnal variation (P < 0.0001). Most eyes showed significant sinusoidal variations in MOR and in pupil size with periods close to 24 hours. On average, MOR oscillated ±0.84 diopters. OAL varied with a period not different from 12 hours. Diurnally varying MOR and OAL were correlated (P = 0.0003, R² = 0.62). However, as previously reported, the variation in OAL did not account for the variation in MOR. From these results, we derived the diurnal variation in ocular power necessary to give the measured MOR variation. CONCLUSIONS: We confirmed a diurnal variation in OAL and found diurnal variations in pupil size and MOR. Although changes in OAL explain the MOR previously observed in response to lenses and diffusers, they do not completely account for the observed diurnal variation of MOR nor for the reduction in hyperopia during normal development. We infer that the diurnal variation in MOR and normal emmetropization both result from small differences in the relative changes of OAL and ocular power.

Longitudinal in vivo imaging of cones in the alert chicken.

PURPOSE: To demonstrate the feasibility of in vivo measurements of cones and their distributions as a function of normal growth without adaptive optics (AO) and also discuss the potential advantages and disadvantages of AO imaging in the chick, an animal model of myopia. METHODS: Chicks were obtained on the day of hatching. Axial length and retinoscopy measurements were performed on days 0 and 14. Chicks were imaged on the day of hatching and 14 days later in a custom-built confocal scanning laser ophthalmoscope. Angular densities, linear cone spacings, and cone packing arrangements were determined. RESULTS: Four subarrays of hexagonally packed cones were identified on both days and, from their angular spacings, appear to correspond to different cone types. There were no significant changes in angular cone density with growth and linear spacings of cones increased with growth. This is true for both overall densities and those of the cone subtypes. There was no change in the percent of hexagonally packed cones with growth. CONCLUSIONS: Cones can be imaged longitudinally in vivo in the awake chick. The packing arrangement of cones is 40% hexagonally packed. Although AO is not necessary to visualize the cones, including the subarrays of like cones, some closely spaced cones of different types may not be resolved. Most importantly, there is a need to use a larger pupil with growth to maintain the same linear resolution in the larger eye. Novel longitudinal imaging techniques and methods in animal models are shown here to give insights into normal development and, in future, will give insights into visual disorders and diseases, including myopia.

Blur on the retina due to higher-order aberrations: comparison of eye growth models to experimental data.

In the simplest model of eye growth, the ocular optics uniformly scale upwards, as do monochromatic higher-order aberrations (HOA) and linear blur on the retina. However, measured HOA remain constant or decrease with growth in some species. A new model, which holds HOA and the associated linear blur on the retina constant, was used to predict changes in HOA and resulting image quality on the retina during growth, in each of chick, monkey, and human. Models used rates of growth in each of the three species. Angular optical quality on the retina due to HOA, and its metrics improved, in contrast to the constancy predicted by uniform scaling. The model with constant linear HOA blur predicts well the improvement in human optical quality between infant and adult. Overall, in chick and monkey, angular blur improves at a rate faster than that predicted by the constant linear blur model, implying that linear retinal blur due to HOA decreases with age. On the other hand, in chick, angular blur due to third-order aberrations decreased at a rate predicted by the constant linear blur model. Growth changes in retinal blur due to HOA are species dependent but can be better understood by comparison with the new model predictions.

Depolarization properties of the optic nerve head: the effect of age.

The degree of polarization (DOP) of the light reflected from the optic nerve head has been assessed by means of a polarimetric scanning laser ophthalmoscope as a function of the age of the participants. Four fundus images corresponding to independent polarization states in the recording pathway were used to compute the spatially-resolved DOP. This was not uniform across the optic nerve head and depended on both the location and the participant's age. Along a peripapillary annulus the DOP followed a double-peak pattern. Moreover, the values along this annulus decreased significantly with increasing age. This depolarization appears to originate in part in the retinal nerve fiber layer. Detailed age-dependent knowledge of the ocular depolarization properties may help to improve clinical diagnosis of the retinal nerve fiber layer.

Characterizing image quality in a scanning laser ophthalmoscope with differing pinholes and induced scattered light.

We quantify the effects on scanning laser ophthalmoscope image quality of controlled amounts of scattered light, confocal pinhole diameter, and age. Optical volumes through the optic nerve head were recorded for a range of pinhole sizes in 12 subjects (19-64 years). The usefulness of various overall metrics in quantifying the changes in fundus image quality is assessed. For registered and averaged images, we calculated signal-to-noise ratio, entropy, and acutance. Entropy was best able to distinguish differing image quality. The optimum confocal pinhole diameter was found to be 50 microm (on the retina), providing improved axial resolution and image quality under all conditions.

Improved scanning laser fundus imaging using polarimetry.

We present a polarimetric technique to improve fundus images that notably simplifies and extends a previous procedure [Opt. Lett.27, 830 (2002)]. A generator of varying polarization states was incorporated into the illumination path of a confocal scanning laser ophthalmoscope. A series of four images, corresponding to independent incoming polarization states, were recorded. From these images, the spatially resolved elements of the top row of the Mueller matrix were computed. From these elements, images with the highest and lowest quality (according to different image quality metrics) were constructed, some of which provided improved visualization of fundus structures of clinical importance (vessels and optic nerve head). The metric values were better for these constructed images than for the initially recorded images and better than averaged images. Entropy is the metric that is most sensitive to differences in the image quality. Improved visualization of features could aid in the detection, localization, and tracking of ocular disease and may be applicable in other biomedical imaging.

Potential effect on the retinoscopic reflex of scleral expansion surgery for presbyopia.

PURPOSE: In this initial study, we model the impact of crystalline lens movement and tilt, which we postulate are a potential consequence of scleral expansion surgery (SES). We demonstrate the possibility that these lead to an improvement in near vision with no concurrent restoration of lens accommodative function. With the implantation of scleral expansion bands (SEB), Schachar predicts an increase in the amplitude of accommodation not observed objectively. We postulate that the SEB implants cause the crystalline lens to be shifted forward and become misaligned. Using mathematical models of the optics of the human eye, we assess the effects of our postulate on the power of the eye, the depth of field, optical aberrations, and the appearance of the horizontal retinoscopic reflex. METHODS: Using anatomically based models of the human eye, the postulated effects of SES are theoretically modeled and optically analyzed in Code V for unintentional lens anterior movement, tilts, and decentrations of up to 1 mm, +/- 3 degrees , and +/- 0.3mm, respectively. The transverse aberrations are calculated before and after SES. Because it has been reported that the appearance of the retinoscopic reflex is consistent with the presence of excess aberrations, we also predict the appearance of the one-dimensional retinoscopic reflex for our models. The change in refractive error is also determined. RESULTS.: Unintentional lens shift, tilt, and decentration, as might occur as a result of SES surgery, would result in an increase in the total power of the eye along with an increase in asymmetric aberrations and little change in symmetric aberrations. The calculated appearances of the retinoscopic reflexes pre- and postsurgery are consistent with observations in the literature. CONCLUSIONS: Scleral expansion surgery could produce an improvement in near vision through an unintentional anterior displacement of the crystalline lens in combination with excess tilts and decentrations rather than as a result of a restoration of lens accommodation. There is a need for measurements and further analysis of the optical and visual properties of SES patients postsurgery.

Aberrations of chick eyes during normal growth and lens induction of myopia.

Understanding the control of eye growth may lead to the prevention of nearsightedness (myopia). Chicks develop refractive errors in response to defocusing lenses by changing the rate of eye elongation. Changes in optical image quality and the optical signal in lens compensation are not understood. Monochromatic ocular aberrations were measured in 16 chicks that unilaterally developed myopia in response to unilateral goggles with -15D lenses and in 6 chicks developing naturally. There is no significant difference in higher-order root mean square aberrations (RMSA) between control eyes of the goggled birds and eyes of naturally developing chicks. Higher-order RMSA for a constant pupil size exponentially decreases in the chick eye with age more slowly than defocus. In the presence of a defocusing lens, the exponential decrease begins after day 2. In goggled eyes, asymmetric aberrations initially increase significantly, followed by an exponential decrease. Higher-order RMSA is significantly higher in goggled eyes than in controls. Equivalent blur, a new measure of image quality that accounts for increasing pupil size with age, exponentially decreases with age. In goggled eyes, this decrease also occurs after day 2. The fine optical structure, reflected in higher-order aberrations, may be important in understanding normal development and the development of myopia.

Optical analysis of an accommodating intraocular lens.

PURPOSE: To model the feasibility of an accommodating intraocular lens (IOL) that allows near vision by means of an anterior translation within the capsular bag. SETTING: University of Waterloo, Waterloo, Ontario, Canada. METHODS: Model eyes were constructed and analyzed based on experimental data using Code V, a computerized optical design tool. The potential near vision of IOLs of different powers was calculated as they were moved anteriorly within the capsular bag. The conditions under which a spherical lens performs well and when an aspheric design should be considered were determined. RESULTS: Accommodation (the dioptric change from the far to the near point) varies linearly with lens movement and is sensitive to corneal and IOL powers. Simple equations were derived and accurately predicted induced accommodation. Retinal image quality varies significantly with pupil size and IOL power. However, image quality is minimally affected by the amount of induced accommodation. CONCLUSIONS: From an optical standpoint accommodation with adequate image quality can be achieved by anterior movement of a spherical IOL within the capsular bag.

Polarization properties of the in vitro old human crystalline lens.

We have studied the spatially resolved polarization properties of the in vitro intact old human crystalline lens (from 56 to 88 years old) by using Mueller-matrix imaging polarimetry. Analysis was performed within an average of 54 h of death. Results show that the overall retardation is small (7 degrees on average) and decreases from the centre of the lens to the periphery. Lenticular birefringence is linear but has a spatial dependence, reducing outwards along the radius. The distribution of azimuthal angle of the birefringent structure of the crystalline lens changes depending on each individual lens. Diattenuation and polarizance were found to be small, however, depolarization was about 35% for the set of lenses studied here.

Confocal scanning laser ophthalmoscopy improvement by use of Mueller-matrix polarimetry.

A new technique for improving the signal-to-noise ratio and the contrast in images recorded with a confocal scanning laser system is presented. The method is based on the incorporation of a polarimeter into the setup. After the spatially resolved Mueller matrix of a sample was calculated, images for incident light with different states of polarization were reconstructed, and both the best and the worst images were computed. In both the microscope and the opthalmoscope modes, the best images are better than the originals. In contrast, the worst images are poorer. This technique may be useful in different fields such as confocal microscopy and retinal imaging.