-
EClinicalMedicine Jan 2022The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients...
BACKGROUND
The hematopoietic stem cell disorders, myeloproliferative neoplasms (MPNs), are characterised by chronic low-grade inflammation (CLI). Recently, we showed that patients with MPNs have an increased prevalence of drusen and age-related macular degeneration (AMD), and drusen prevalence seemed associated with higher CLI. Studying MPNs may reveal more about drusen pathophysiology. This study investigated CLI further by measuring cytokine levels and complement system markers, comparing these between patients with MPNs and AMD.
METHODS
This cross-sectional study, between July 2018 and November 2020 conducted at Zealand University Hospital (ZUH) - Roskilde, Denmark, included 29 patients with neovascular AMD (nAMD), 28 with intermediate-stage AMD (iAMD), 62 with MPNs (35 with drusen - MPNd and 27 with healthy retinas - MPNn). With flow cytometry, we measured complement-regulatory-proteins (Cregs). With immunoassays, we investigated cytokine levels combined into a summary-inflammation-score (SIS).
FINDINGS
The MPNd and nAMD groups had similar SIS, significantly higher than the MPNn and iAMD groups. Additionally, we found SIS to increase over the MPN biological continuum from early cancer stage, essential thrombocytaemia (ET), over polycythaemia vera (PV) to the late-stage primary myelofibrosis (PMF). MPNs showed signs of complement dysregulation, with Cregs expression lower in PV than ET and PMF and even lower in PV patients with drusen.
INTERPRETATION
This study suggests that MPNd have a higher CLI than MPNn and may indicate systemic CLI to play a greater part in, and even initiate drusen formation. We suggest using MPNs as a "Human Inflammation Model" of drusen development. The CLI in MPNs elicits drusen formation, triggering more CLI creating a vicious cycle, increasing the risk of developing AMD.
FUNDING
Fight for Sight, Denmark, and Region Zealand's research promotion fund.
PubMed: 35128362
DOI: 10.1016/j.eclinm.2021.101248 -
Investigative Ophthalmology & Visual... Feb 2020To characterize the evolution and structure of soft drusen in aged rhesus macaques using in vivo multimodal retinal imaging and ex vivo histologic and ultrastructural...
PURPOSE
To characterize the evolution and structure of soft drusen in aged rhesus macaques using in vivo multimodal retinal imaging and ex vivo histologic and ultrastructural analyses as a nonhuman primate model of early age-related macular degeneration (AMD).
METHODS
Multimodal imaging including fundus photography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were used to characterize and track individual drusen lesions in 20 aged rhesus macaques (mean age 23.3 ± 2.7 years) with drusenoid lesions over 2 years, followed by semithin histologic analysis and transmission electron microscopy (TEM).
RESULTS
Although most drusen gradually increased in size, a portion spontaneously regressed or collapsed over 2 years. Histologic analyses showed that soft drusen exhibit hypertrophy and dysmorphia of overlying retinal pigment epithelium (RPE), as seen in early and intermediate AMD, but do not exhibit RPE atrophy, RPE migration, or photoreceptor degeneration characteristic of advanced AMD. Ultrastructure of soft drusen showed abundant lipid particles within Bruch's membrane and AMD-related basal linear deposits (BlinD) resembling those in human drusen.
CONCLUSIONS
The dynamic remodeling, histologic findings, and ultrastructural features of soft drusen in aged rhesus macaques support nonhuman primates as an animal model of early AMD and reveal important insights into drusen biogenesis and AMD development.
Topics: Animals; Bruch Membrane; Disease Models, Animal; Fluorescein Angiography; Geographic Atrophy; Macaca mulatta; Retinal Drusen; Retinal Pigment Epithelium; Tomography, Optical Coherence
PubMed: 32084273
DOI: 10.1167/iovs.61.2.32 -
Journal of Neuro-ophthalmology : the... Mar 2012The fluorescein angiographic criteria for differentiating optic disc drusen (ODD) from optic disc edema have been unclear. We designed a study to identify distinguishing... (Review)
Review
BACKGROUND
The fluorescein angiographic criteria for differentiating optic disc drusen (ODD) from optic disc edema have been unclear. We designed a study to identify distinguishing angiographic features of each and to apply them to cases where both drusen and edema were present.
METHODS
A computer search was performed for cases evaluated in a university academic neuro-ophthalmology consultative practice and coded as ODD; all cases were reviewed, and those with fluorescein angiography were selected for further study. Cases were classified as either buried or surface ODD. Ten cases with papilledema were selected for comparison. Eight cases of coexistent drusen and edema were identified. Autofluorescence, early leakage, early blockage, early and late nodular staining, late peripapillary staining, and late leakage were tabulated.
RESULTS
Two hundred sixteen cases of ODD were identified; 62 (116 eyes) had adequate fluorescein angiography for study. Twenty-three eyes were classified as surface ODD; 90% demonstrated early nodular staining of the disc, with late nodular staining in 90% and late circumferential peripapillary staining in 22%; autofluorescence was visible in 93% with preinjection photography. Eighty-three eyes were classified as buried ODD; 25% demonstrated early nodular staining, with late nodular staining in 29% and late circumferential peripapillary staining in 80%; autofluorescence was visible in 12% of those with preinjection photography. In 9 eyes, buried ODD were present with superimposed true edema. In these eyes, early dye leakage, late nodular hyperfluorescence, and late leakage were present.
CONCLUSION
Early and late fluorescein angiographic features reliably distinguish ODD from edema and may be particularly useful when the conditions coexist.
Topics: Adolescent; Adult; Aged; Child; Diagnosis, Differential; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Optic Disk; Optic Disk Drusen; Papilledema; Retinal Artery; Retrospective Studies; Young Adult
PubMed: 21926917
DOI: 10.1097/WNO.0b013e31823010b8 -
Biomedical Optics Express Mar 2023Qualitative and quantitative assessments of calcified drusen are clinically important for determining the risk of disease progression in age-related macular degeneration...
Qualitative and quantitative assessments of calcified drusen are clinically important for determining the risk of disease progression in age-related macular degeneration (AMD). This paper reports the development of an automated algorithm to segment and quantify calcified drusen on swept-source optical coherence tomography (SS-OCT) images. The algorithm leverages the higher scattering property of calcified drusen compared with soft drusen. Calcified drusen have a higher optical attenuation coefficient (OAC), which results in a choroidal hypotransmission defect (hypoTD) below the calcified drusen. We show that it is possible to automatically segment calcified drusen from 3D SS-OCT scans by combining the OAC within drusen and the hypoTDs under drusen. We also propose a correction method for the segmentation of the retina pigment epithelium (RPE) overlying calcified drusen by automatically correcting the RPE by an amount of the OAC peak width along each A-line, leading to more accurate segmentation and quantification of drusen in general, and the calcified drusen in particular. A total of 29 eyes with nonexudative AMD and calcified drusen imaged with SS-OCT using the 6 × 6 mm scanning pattern were used in this study to test the performance of the proposed automated method. We demonstrated that the method achieved good agreement with the human expert graders in identifying the area of calcified drusen (Dice similarity coefficient: 68.27 ± 11.09%, correlation coefficient of the area measurements: r = 0.9422, the mean bias of the area measurements = 0.04781 mm).
PubMed: 36950236
DOI: 10.1364/BOE.485999 -
Acta Ophthalmologica Dec 2022To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort.
PURPOSE
To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort.
METHODS
This was a single-centre, cross-sectional, classical twin study with ophthalmic examination including refraction, biometry, best-corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location.
RESULTS
The study enrolled 176 same-sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 μm), ≥20 small hard extramacular drusen, intermediate drusen (63-125 μm) anywhere, and large drusen (>125 μm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5-82.9], 69.1% [62.3-75.9], 30.1% [4.1-56.1], and 65.6% [26.4-100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier.
CONCLUSION
Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.
Topics: Humans; Retinal Drusen; Cross-Sectional Studies; Macular Degeneration; Geographic Atrophy; Twins, Monozygotic; Tomography, Optical Coherence
PubMed: 35322936
DOI: 10.1111/aos.15136 -
Frontiers in Immunology 2018Age-related macular degeneration (AMD), a retinal degenerative disease, is the leading cause of central vision loss among the elderly population in developed countries... (Review)
Review
Age-related macular degeneration (AMD), a retinal degenerative disease, is the leading cause of central vision loss among the elderly population in developed countries and an increasing global burden. The major risk is aging, compounded by other environmental factors and association with genetic variants for risk of progression. Although the etiology of AMD is not yet clearly understood, several pathogenic pathways have been proposed, including dysfunction of the retinal pigment epithelium, inflammation, and oxidative stress. The identification of AMD susceptibility genes encoding complement factors and the presence of complement and other inflammatory mediators in drusen, the hallmark deposits of AMD, support the concept that local inflammation and immune-mediated processes play a key role in AMD pathogenesis that may be accelerated through systemic immune activation. In this regard, increased levels of circulating C-reactive protein (CRP) have been associated with higher risk of AMD. Besides being a risk marker for AMD, CRP may also play a role in the progression of the disease as it has been identified in drusen, and we have recently found that its monomeric form (mCRP) induces blood retinal barrier disruption . In this review, we will address recent evidence that links CRP and AMD pathogenesis, which may open new therapeutic opportunities to prevent the progression of AMD.
Topics: Aged; C-Reactive Protein; Complement System Proteins; Disease Progression; Humans; Inflammation; Macular Degeneration; Molecular Targeted Therapy; Oxidative Stress; Retinal Drusen; Retinal Pigment Epithelium; Risk Factors
PubMed: 29725335
DOI: 10.3389/fimmu.2018.00808 -
Ophthalmology. Retina Feb 2023To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD).
PURPOSE
To identify the prevalence of extramacular drusen and their role in the progression of age-related macular degeneration (AMD).
DESIGN
Retrospective analysis of a prospective cohort study.
PARTICIPANTS
The study was conducted in 4168 eyes (2998 participants) with intermediate AMD in one or both eyes enrolled in the Age-Related Eye Disease Study 2 (AREDS2), a 5-year multicenter study of nutritional supplements.
METHODS
Baseline 3-field 30-degree color photographs were evaluated for drusen characteristics outside the macular grid, including size, area, and location. The characteristics of extramacular drusen were compared with those of drusen within the macula.
MAIN OUTCOME MEASURES
Progression rates to late AMD.
RESULTS
Although extramacular drusen were observed in 3624 (86.9%) eyes, they represented a small area (< 0.5 mm) in 50.3% of eyes, with only 17.5% exhibiting an area of > 1 disc area. Eyes with extramacular drusen exhibited larger macular drusen size and area than eyes without extramacular drusen (P < 0.001). Extramacular drusen were not associated with progression to late AMD. The hazard ratio adjusted for baseline age, sex, smoking, AMD severity level, and reticular pseudodrusen for 4043 eyes at risk of developing late AMD over 5 years was 1.17 (95% confidence interval [CI], 0.88-1.54; P = 0.27) for geographic atrophy and 0.96 (95% CI, 0.76-1.2; P = 0.7) for neovascular AMD.
CONCLUSIONS
Extramacular drusen are commonly observed in eyes with AMD and are more frequent with an increasing drusen burden within the macula. In eyes with intermediate AMD, extramacular drusen do not confer additional risk to previously identified risk factors in progression to late AMD.
Topics: Humans; Angiogenesis Inhibitors; Prospective Studies; Retinal Drusen; Retrospective Studies; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration; Macular Degeneration
PubMed: 35940477
DOI: 10.1016/j.oret.2022.08.001 -
Translational Vision Science &... Apr 2020To investigate the autofluorescence lifetimes as well as spectral characteristics of soft drusen and retinal hyperpigmentation in age-related macular degeneration (AMD).
PURPOSE
To investigate the autofluorescence lifetimes as well as spectral characteristics of soft drusen and retinal hyperpigmentation in age-related macular degeneration (AMD).
METHODS
Forty-three eyes with nonexudative AMD were included in this study. Fluorescence lifetime imaging ophthalmoscopy (FLIO), which detects autofluorescence decay over time in the short (SSC) and long (LSC) wavelength channel, was performed. The mean autofluorescence lifetime (τ) and the spectral ratio (sr) of autofluorescence emission in the SSC and LSC were recorded and analyzed. In total, 2760 soft drusen and 265 hyperpigmented areas were identified from color fundus photographs and spectral domain optical coherence tomography (SD-OCT) images and superimposed onto their respective AF images. τ and sr of these lesions were compared with fundus areas without drusen. For clearly hyperfluorescent drusen, the local differences compared to fundus areas without drusen were determined for lifetimes and sr.
RESULTS
Hyperpigmentation showed significantly longer τ (SSC: 341 ± 81 vs. 289 ± 70 ps, < 0.001; LSC: 406 ± 42 vs. 343 ± 42 ps, < 0.001) and higher sr (0.621 ± 0.077 vs. 0.539 ± 0.083, < 0.001) compared to fundus areas without hyperpigmentation or drusen. No significant difference in τ was found between soft drusen and fundus areas without drusen. However, the sr was significantly higher in soft drusen (0.555 ± 0.077 vs. 0.539 ± 0.081, < 0.0005). Hyperfluorescent drusen showed longer τ than surrounding fundus areas without drusen (SSC: 18 ± 42 ps, = 0.074; LSC: 16 ± 29 ps, = 0.020).
CONCLUSIONS
FLIO can quantitatively characterize the autofluorescence of the fundus, drusen, and hyperpigmentation in AMD.
TRANSLATIONAL RELEVANCE
The experimental FLIO technique was applied in a clinical investigation. As FLIO yields information on molecular changes in AMD, it might support future diagnostics.
Topics: Fluorescein Angiography; Humans; Hyperpigmentation; Macular Degeneration; Ophthalmoscopy; Retinal Drusen
PubMed: 32821492
DOI: 10.1167/tvst.9.5.20 -
Scientific Reports Apr 2022This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen...
This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen (RPD). Clinical records of patients diagnosed with CD or RPD with multimodal imaging was reviewed for patients diagnosed with both CD and RPD. The distribution patterns of CD (macular and diffuse type) and RPD (localized, intermediate, and diffuse type), presence of soft drusen, large drusen (> 200 µm), variant subretinal drusenoid deposits, and macular complications were investigated. Of the 220 eyes of 110 patients diagnosed with CD and 926 eyes of 463 patients diagnosed with RPD, 13 eyes of seven patients met the diagnostic criteria for both CD and RPD. The mean age at initial presentation was 71.4 ± 8.8 years and six patients were female. The mean subfoveal choroidal thickness was 143.8 ± 25.1 µm. The distribution of CD was of the macular type in all eyes. Distribution of RPD was localized in 11 eyes (84.6%) and intermediate in two eyes (15.4%). Soft drusen, large drusen, and variant subretinal drusenoid deposits were present in 13 (100%), 12 (92.3%) and, seven (53.8%) eyes, respectively. Macular neovascularization was observed in two eyes (15.4%). CD and RPD can coexist in eyes with AMD. Multimodal imaging should be used for AMD eyes with features suggestive of CD and RPD, considering the high likelihood of developing late AMD.
Topics: Choroid; Female; Fluorescein Angiography; Humans; Macular Degeneration; Retina; Retinal Drusen; Tomography, Optical Coherence
PubMed: 35383241
DOI: 10.1038/s41598-022-09608-9 -
Eye (London, England) Jan 2022
Topics: Humans; Retina; Retinal Drusen
PubMed: 34045685
DOI: 10.1038/s41433-021-01574-2