Longitudinal retinal layer changes in preclinical Alzheimer's disease.

PURPOSE: Several studies found reduced retinal thickness on optical coherence tomography (OCT) in Alzheimer's disease (AD), even in preclinical stages, labelling this technique of interest as biomarker. In this study, we examine retinal thickness changes in preclinical AD, as defined by cognitively normal individuals with amyloid-beta (Aß) on positron emission tomography (PET). METHODS: For this monocentre study, 145 cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the EMIF-AD PreclinAD study. At baseline, participants underwent [18 F] flutemetamol PET that was visually rated for cortical Aß. Binding potential was calculated as continuous measure for Aß. Optical coherence tomography (OCT) was performed at baseline and after 22 months to assess changes in total and individual inner retinal layer thickness in the macular region (ETDRS circles) and peripapillary retinal nerve fibre layer thickness. Differences in rate of change between amyloid-beta positive and negative individuals and associations between binding potential and change in retinal thickness were evaluated. RESULTS: Sixteen participants (11%) were positive for Aß. Change in retinal thickness did not differ in any region between Aß+ and Aß- individuals. A positive association between binding potential and change in inner plexiform layer thickness was observed in the inner macular ring (beta = 1.708, CI = 0.575 to 2.841, p = 0.003). CONCLUSION: Aß+ individuals did not differ in rate of change of any retinal layer compared to controls, but higher binding potential at baseline was associated with less IPL thinning over time. Optical coherence tomography (OCT) as a longitudinal screening tool for preclinical AD seems limited, but IPL changes offer leads for further research.

Subretinal Fibrosis Detection Using Polarization Sensitive Optical Coherence Tomography.

Purpose: Subretinal fibrosis (SRFib) is an important cause of permanent loss-of-vision diseases with submacular neovascularization, but a reliable diagnostic method is currently missing. This study uses polarization-sensitive optical coherence tomography (PS-OCT) to detect SRFib within retinal lesions by measurement of its birefringent collagen fibers. Methods: Twenty-five patients were enrolled with retinal pathology in one or both eyes containing (1) suspected SRFib, (2) lesions suspected not to be fibrotic, or (3) lesions with doubtful presence of SRFib. All eyes were evaluated for SRFIb using conventional diagnostics by three retinal specialists. PS-OCT images were visually evaluated for SRFib based on cumulative phase retardation, local birefringence, and optic axis uniformity. Results: Twenty-nine eyes from 22 patients were scanned successfully. In 13 eyes, SRFib was diagnosed by all retinal specialists; of these, 12 were confirmed by PS-OCT and one was inconclusive. In nine eyes, the retinal specialists expected no SRFib, which was confirmed by PS-OCT in all cases. In seven eyes, the retinal specialists' evaluations were inconsistent with regard to the presence of SRFib. PS-OCT confirmed the presence of SRFib in four of these eyes and the absence of SRFib in two eyes and was inconclusive in one eye. Conclusions: In 21 out of 22 eyes, PS-OCT confirmed the evaluation of retinal specialists regarding the presence of SRFib. PS-OCT provided additional information to distinguish SRFib from other tissues within subretinal neovascular lesions in 6 out of 7 eyes. Translational Relevance: PS-OCT can identify and quantify SRFib in doubtful cases for which a reliable diagnosis is currently lacking.

Ocular biomarkers for cognitive impairment in nonagenarians; a prospective cross-sectional study.

BACKGROUND: Ocular imaging receives much attention as a source of potential biomarkers for dementia. In the present study, we analyze these ocular biomarkers in cognitively impaired and healthy participants in a population aged over 90 years (= nonagenarian), and elucidate the effects of age on these biomarkers. METHODS: For this prospective cross-sectional study, we included individuals from the EMIF-AD 90+ study, consisting of a cognitively healthy (N = 67) and cognitively impaired group (N = 33), and the EMIF-AD PreclinAD study, consisting of cognitively healthy controls aged ≥60 (N = 198). Participants underwent Optical Coherence Tomography (OCT) and fundus photography of both eyes. OCT was used to asses total and individual inner retinal layer thickness in the macular region (Early Treatment Diabetic Retinopathy Study circles) as well as peripapillary retinal nerve fiber layer thickness, fundus images were analyzed with Singapore I Vessel Assessment to obtain 7 retinal vascular parameters. Values for both eyes were averaged. Differences in ocular biomarkers between the 2 nonagenarian groups were analyzed using linear regression, differences between the individual nonagenarian groups and controls were analyzed using generalized estimating equations. RESULTS: Ocular biomarkers did not differ between the healthy and cognitively impaired nonagenarian groups. 19 out of 22 ocular biomarkers assessed in this study differed between either nonagenarian group and the younger controls. CONCLUSION: The ocular biomarkers assessed in this study were not associated with cognitive impairment in nonagenarians, making their use as a screening tool for dementing disorders in this group limited. However, ocular biomarkers were significantly associated with chronological age, which were very similar to those ascribed to occur in Alzheimer's Disease.

The spatial relation of diabetic retinal neurodegeneration with diabetic retinopathy.

PURPOSE: Diabetic retinal neurodegeneration (DRN) has been demonstrated in eyes of patients with diabetes mellitus (DM), even in the absence of diabetic retinopathy (DR). However, no studies have looked at the rate of change in retinal layers and presence/development of DR over time per quadrant of the macula. In this longitudinal study, we aimed to clarify whether the rate of DRN is associated with the development/presence of DR within 4 different quadrants of the retina. METHODS: 80 eyes of 40 patients with type 1 DM and no/minimal DR were included. At 4 visits over 6 years, SD-OCT and fundus images were acquired. Thickness of the Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL) and Inner Plexiform Layer (IPL) was measured in a 1-6mm circle around the fovea overall and for each quadrant (superior, nasal, inferior, temporal). Fundus images were scored for the presence/absence of DR in these areas. Multilevel analyses were performed to determine the rate of change for each layer overall and per quadrant for eyes/quadrants without and with DR during the follow-up period. RESULTS: RNFL and GCL showed significant thinning over time, IPL significant thickening. These changes were more pronounced for GCL and IPL in eyes/quadrants with DR during the follow-up period. CONCLUSIONS: RNFL and GCL both showed thinning over time, which was more pronounced in eyes with DR for GCL. This holds true even in regional parts of the retina, as quadrant analyses showed similar results, showing that structural DRN is associated with DR per quadrant independently.

Optic axis uniformity as a metric to improve the contrast of birefringent structures and analyze the retinal nerve fiber layer in polarization-sensitive optical coherence tomography.

A new metric is used to improve the contrast of birefringent structures in biological tissue using polarization-sensitive optical coherence tomography. This metric, optic axis uniformity (OAxU), is based on the optic axis of birefringence and quantifies the uniformity of the optic axis direction. OAxU provides surprisingly strong contrast for fibrous structures such as muscle and the retinal nerve fiber layer (RNFL). We used OAxU for automatic segmentation of the RNFL in human eyes. From the segmentation, en face images of RNFL thickness and RNFL birefringence were created. The measured birefringence values are consistent with earlier reports.

Retinal thickness as a potential biomarker in patients with amyloid-proven early- and late-onset Alzheimer's disease.

Introduction: Retinal thickness measured with optical coherence tomography has been proposed as a noninvasive biomarker for Alzheimer's disease (AD). We therefore measured retinal thickness in well-characterized AD and control participants, considering ophthalmological confounders. Methods: We included 57 amyloid-proven AD cases and 85 cognitively normal, amyloid-negative controls. All subjects underwent retinal thickness measurements with spectral domain optical coherence tomography and an ophthalmological assessment to exclude ocular disease. Results: Retinal thickness did not discriminate cases from controls, including stratified analyses for early- versus late-onset AD. We found significant associations between macular thickness and global cortical atrophy [ß -0.358; P = .01] and parietal cortical atrophy on magnetic resonance imaging [ß -0.371; P < .01] in AD cases. Discussion: In this study, representing the largest optical coherence tomography cohort with amyloid-proven AD cases, we show that retinal thickness does not discriminate AD from controls, despite evident changes on clinical, neuroimaging, and CSF measures, querying the use of retinal thickness measurements as an AD biomarker.

Is retinal vasculature a biomarker in amyloid proven Alzheimer's disease?

Introduction: The retina is a potential source of noninvasive vascular biomarkers for Alzheimer's disease (AD). We assessed retinal microvasculature in well-characterized AD cases, taking ophthalmological confounders into account. Methods: We included 48 amyloid-positive AD patients and 38 amyloid-negative cognitively normal control subjects. All participants underwent ophthalmological screening to exclude interfering ocular disease. Using a multimodal approach, we measured retinal vascular parameters, choroidal thickness, macular vascular density, and foveal avascular zone size. Results: We found no disease effects on retinal vascular measures (all ß's < |0.15|, all P > .2), adjusted for confounders. Venular tortuosity was inversely associated with Fazekas score in control subjects (ß -0.56, P < .01), while vessel density in the outer ring of the macula was inversely associated with Fazekas score in AD cases (ß -0.64, P < .01). Discussion: In conclusion, retinal vasculature did not discriminate patients with AD from control subjects, despite evident changes on clinical, neuroimaging, and cerebrospinal fluid biomarkers, challenging the use of retinal vasculature measurements as AD biomarker.

Retinal layer thickness in preclinical Alzheimer's disease.

PURPOSE: There is urgent need for non-invasive diagnostic biomarkers in the preclinical phase of Alzheimer's Disease (AD). Several studies suggest that retinal thickness is reduced in AD. Here, we aim to test the diagnostic value of retinal thickness in preclinical AD, as defined by cognitively normal individuals with amyloid pathology on PET. METHODS: One hundred and sixty five cognitively healthy monozygotic twins aged ≥ 60 were included from the Netherlands Twin Register taking part in the European Medical Information Framework for Alzheimer's Disease PreclinAD study. Participants underwent [18 F] flutemetamol PET that was visually rated for presence or absence of cortical amyloid beta (Aß). Binding potential (BPND ) was calculated as continuous measure for Aß. Spectral Domain OCT was used to asses total and individual inner retinal layer thickness in the macular region (ETDRS circles) as well as peripapillary retinal nerve fibre layer (pRNFL) thickness. Differences between Aß+ and Aß- individuals and associations between BPND and retinal thickness were analyzed. RESULTS: No differences were found in retinal layer thickness in the macula or pRNFL between Aß+ and Aß- individuals. A positive associations between BPND and macular total retinal thickness was observed in the inner ring (p = 0.018), but this was not statistically significant after correction for multiple testing (p = 0.144). Brain/eye parameters had moderate to high intra-twin correlations (p < 0.001) except visual rating score of Aß, which did not correlate (r = 0.21, p = 0.068). CONCLUSION: Variation in retinal thickness likely reflects genetic differences between individuals, but cannot discriminate between healthy and preclinical AD cases, making its use as biomarker in these early stages limited.

Retinal and Cerebral Microvasculopathy: Relationships and Their Genetic Contributions.

Purpose: Retinal microvasculopathy may reflect small vessel disease in the brain. Here we test the relationships between retinal vascular parameters and small vessel disease, the influence of cardiovascular risk factors on these relationships, and their common genetic background in a monozygotic twin cohort. Methods: We selected 134 cognitively healthy individuals (67 monozygotic twin pairs) aged ≥60 years from the Netherlands Twin Register for the EMIF-AD PreclinAD study. We measured seven retinal vascular parameters averaged over both eyes using fundus images analyzed with Singapore I Vessel Assessment. Small vessel disease was assessed on MRI by a volumetric measurement of periventricular and deep white matter hyperintensities. We calculated associations between RVPs and WMH, estimated intratwin pair correlations, and performed twin-specific analyses on relationships of interest. Results: Deep white matter hyperintensities volume was positively associated with retinal tortuosity in veins (P = 0.004) and fractal dimension in arteries (P = 0.001) and veins (P = 0.032), periventricular white matter hyperintensities volume was positively associated with retinal venous width (P = 0.028). Intratwin pair correlations were moderate to high for all small vessel disease/retinal vascular parameter variables (r = 0.49-0.87, P < 0.001). Cross-twin cross-trait analyses showed that retinal venous tortuosity of twin 1 could predict deep white matter hyperintensities volume of the co-twin (r = 0.23, P = 0.030). Within twin-pair differences for retinal venous tortuosity were associated with within twin-pair differences in deep white matter hyperintensities volume (r = 0.39, P = 0.001). Conclusions: Retinal arterial fractal dimension and venous tortuosity have associations with deep white matter hyperintensities volume. Twin-specific analyses suggest that retinal venous tortuosity and deep white matter hyperintensities volume have a common etiology driven by both shared genetic factors and unique environmental factors, supporting the robustness of this relationship.

The EMIF-AD PreclinAD study: study design and baseline cohort overview.

BACKGROUND: Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. METHODS: From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. RESULTS: We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. CONCLUSIONS: A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.

Retinal thickness correlates with parietal cortical atrophy in early-onset Alzheimer's disease and controls.

INTRODUCTION: The retina may reflect Alzheimer's disease (AD) neuropathological changes and is easily visualized with optical coherence tomography (OCT). Retinal thickness decrease has been correlated to AD, however, without information on amyloid status. We correlated retinal (layer) thickness to AD biomarkers in amyloid-positive early-onset AD (EOAD) patients and amyloid-negative controls. METHODS: We measured macular thickness and peripapillary retinal nerve fiber layer thickness with OCT in 15 EOAD patients and 15 controls and correlated retinal thickness to visual rating scores for atrophy on magnetic resonance imaging. RESULTS: Total macular thickness correlated to parietal cortical atrophy in both groups (Spearman ρ -0.603, P = .001). Macular and peripapillary retinal nerve fiber layer thicknesses were not significantly decreased in EOAD compared to controls. DISCUSSION: Retinal thickness does not discriminate EOAD from controls but is correlated to parietal cortical atrophy in both groups. These findings may suggest reflection of cerebral cortical changes in the retina, independent of amyloid.