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

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. 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. 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. 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 amyloi

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

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 colla-gen 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

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

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 β′s .2), adjusted for confounders. Venular tortuosity was inversely associated with Fazekas score in control subjects (β −0.56, P < .01), while vessel density in the outer ring of the macula was inversely associated with Fazekas score in AD cases (β −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

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 (Aβ) 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 [18F] flutemetamol PET that was visually rated for cortical Aβ. Binding potential was calculated as continuous measure for Aβ. 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 Aβ. Change in retinal thickness did not differ in any region between Aβ+ and Aβ− 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: Aβ+ 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

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 (Aβ) 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 [ 18F] flutemetamol PET that was visually rated for cortical Aβ. Binding potential was calculated as continuous measure for Aβ. 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 Aβ. Change in retinal thickness did not differ in any region between Aβ+ and Aβ− 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: Aβ+ 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

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 [β −0.358; P =.01] and parietal cortical atrophy on magnetic resonance imaging [β −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

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

Optical coherence tomography angiography in preclinical Alzheimer's disease

BACKGROUND/AIMS: As a protrusion from the brain, the retina might reflect the status of the brain. Previous studies showed a decrease in vessel density and foveal avascular zone (FAZ) enlargement on optical coherence tomography angiography (OCTA) in individuals suffering from Alzheimer's disease (AD). This study aims to assess whether such changes are already present in preclinical stages of AD, in a population of monozygotic (MZ) twins. METHODS: 124 cognitively healthy individuals (MZ twins, ages 60-93 years) underwent [18F]flutemetamol amyloid positron emission tomography (PET) scanning and OCTA. PET scans were visually rated for cortical amyloid-beta (Aβ) positivity. Parametric global cortical non-displaceable binding potential (BPND) was used as a continuous measure for Aβ aggregation. FAZ size and vessel densities for the inner and outer ring of the macular ETDRS grid and in a 3-6 mm ring around the optic nerve head (ONH) were measured.OCTA measures were associated with visual Aβ score, BPND and amyloid load estimated by twin concordance on visual Aβ score. Twin correlations were estimated as a measure of maximum heritability of OCTA measures. RESULTS: 13 of 124 participants were Aβ+. Aβ+ individuals had significantly higher vessel density than Aβ- individuals in all regions but did not differ in FAZ size. Twin analyses showed a positive association between and vessel densities in all regions. BPND tended to be associated with higher vessel density in the inner ring. Twin correlations were moderate/high for all OCTA parameters except vessel density around the ONH, which correlated weakly. CONCLUSION: Retinal vessel density was higher in individuals with preclinical AD