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Investigative Ophthalmology & Visual... May 2024To demonstrate the first near-infrared adaptive optics fluorescence lifetime imaging ophthalmoscopy (NIR-AOFLIO) measurements in vivo of the human retinal pigment...
PURPOSE
To demonstrate the first near-infrared adaptive optics fluorescence lifetime imaging ophthalmoscopy (NIR-AOFLIO) measurements in vivo of the human retinal pigment epithelial (RPE) cellular mosaic and to visualize lifetime changes at different retinal eccentricities.
METHODS
NIR reflectance and autofluorescence were captured using a custom adaptive optics scanning light ophthalmoscope in 10 healthy subjects (23-64 years old) at seven eccentricities and in two eyes with retinal abnormalities. Repeatability was assessed across two visits up to 8 weeks apart. Endogenous retinal fluorophores and hydrophobic whole retinal extracts of Abca4-/- pigmented and albino mice were imaged to probe the fluorescence origin of NIR-AOFLIO.
RESULTS
The RPE mosaic was resolved at all locations in five of seven younger subjects (<35 years old). The mean lifetime across near-peripheral regions (8° and 12°) was longer compared to near-foveal regions (0° and 2°). Repeatability across two visits showed moderate to excellent correlation (intraclass correlation: 0.88 [τm], 0.75 [τ1], 0.65 [τ2], 0.98 [a1]). The mean lifetime across drusen-containing eyes was longer than in age-matched healthy eyes. Fluorescence was observed in only the extracts from pigmented Abca4-/- mouse.
CONCLUSIONS
NIR-AOFLIO was repeatable and allowed visualization of the RPE cellular mosaic. An observed signal in only the pigmented mouse extract infers the fluorescence signal originates predominantly from melanin. Variations observed across the retina with intermediate age-related macular degeneration suggest NIR-AOFLIO may act as a functional measure of a biomarker for in vivo monitoring of early alterations in retinal health.
Topics: Humans; Retinal Pigment Epithelium; Ophthalmoscopy; Adult; Middle Aged; Animals; Female; Mice; Male; Young Adult; Optical Imaging; Reproducibility of Results; Infrared Rays; ATP-Binding Cassette Transporters; Fluorescein Angiography
PubMed: 38758638
DOI: 10.1167/iovs.65.5.27 -
Cureus Apr 2024Angioid streaks (AS) are recognized as irregular, linear dehiscences of Bruch's membrane, often associated with systemic diseases. We present the case of a 50-year-old...
Angioid streaks (AS) are recognized as irregular, linear dehiscences of Bruch's membrane, often associated with systemic diseases. We present the case of a 50-year-old woman initially diagnosed with AS during a routine optometric examination. Subsequent ophthalmological evaluation revealed bilateral AS with calcified drusen. Two years post-diagnosis, she developed blurred vision in her right eye due to the choroidal neovascular membrane adjacent to the macular AS. Further evaluation uncovered clinical signs consistent with pseudoxanthoma elasticum (PXE), including characteristic skin lesions. A multidisciplinary approach involving ophthalmology, dermatology, and cardiovascular specialists was initiated. Histopathological confirmation of PXE was obtained through a skin biopsy. PXE, an autosomal recessive disorder characterized by elastin calcification, presents systemic manifestations necessitating comprehensive evaluation and monitoring. This case demonstrates the importance of recognizing ocular complications in PXE and advocates for early multidisciplinary intervention to mitigate potential vision and life-threatening outcomes.
PubMed: 38741802
DOI: 10.7759/cureus.58104 -
Cureus Apr 2024Sorsby macular dystrophy is an autosomal dominant disorder secondary to heterozygous mutations in the TIMP3 gene in 22q12. It begins with fine, pale, drusen-like...
Sorsby macular dystrophy is an autosomal dominant disorder secondary to heterozygous mutations in the TIMP3 gene in 22q12. It begins with fine, pale, drusen-like deposits or confluent, faint yellow material or sheets beneath the retinal pigment epithelium, but it eventually progresses to either geographic atrophy with pigmentary clumps or scars due to the choroidal neovascular membrane around the fourth decade of life. We describe a patient who presented with a progressive loss of unilateral visual acuity, wrongly suggesting an infectious or inflammatory disease.
PubMed: 38738028
DOI: 10.7759/cureus.57976 -
Diagnostics (Basel, Switzerland) Apr 2024Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy.... (Review)
Review
Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy. These conditions are distinguished by bilateral and relatively symmetrical abnormalities in the macula that significantly impair central visual function. Recent strides in fundus imaging, especially optical coherence tomography (OCT), have enhanced our comprehension and diagnostic capabilities for MD. OCT enables the identification of neurosensory retinal disorganization patterns and the extent of damage to retinal pigment epithelium (RPE) and photoreceptor cells in the dystrophies before visible macular pathology appears on fundus examinations. It not only helps us in diagnostic retinal and choroidal pathologies but also guides us in monitoring the progression of, staging of, and response to treatment. In this review, we summarize the key findings on OCT in some of the most common MD.
PubMed: 38732293
DOI: 10.3390/diagnostics14090878 -
International Journal of Molecular... Apr 2024Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of...
Age-related macular degeneration (AMD) is an age-related disorder that is a global public health problem. The non-enzymatic Maillard reaction results in the formation of advanced glycation end products (AGEs). Accumulation of AGEs in drusen plays a key role in AMD. AGE-reducing drugs may contribute to the prevention and treatment of AGE-related disease. Fructosamine oxidase (FAOD) acts on fructosyl lysine and fructosyl valine. Based upon the published results of fructosamine 3-kinase (FN3K) and FAOD obtained in cataract and presbyopia, we studied ex vivo FAOD treatment as a non-invasive AMD therapy. On glycolaldehyde-treated porcine retinas, FAOD significantly reduced AGE autofluorescence ( = 0.001). FAOD treatment results in a breakdown of AGEs, as evidenced using UV fluorescence, near-infrared microspectroscopy on stained tissue sections of human retina, and gel permeation chromatography. Drusen are accumulations of AGEs that build up between Bruch's membrane and the retinal pigment epithelium. On microscopy slides of human retina affected by AMD, a significant reduction in drusen surface to 45 ± 21% was observed following FAOD treatment. Enzymatic digestion followed by mass spectrometry of fructose- and glucose-based AGEs (produced in vitro) revealed a broader spectrum of substrates for FAOD, as compared to FN3K, including the following: fructosyllysine, carboxymethyllysine, carboxyethyllysine, and imidazolone. In contrast to FN3K digestion, agmatine (4-aminobutyl-guanidine) was formed following FAOD treatment in vitro. The present study highlights the therapeutic potential of FAOD in AMD by repairing glycation-induced damage.
Topics: Macular Degeneration; Humans; Glycation End Products, Advanced; Animals; Swine; Retina; Amino Acid Oxidoreductases
PubMed: 38732004
DOI: 10.3390/ijms25094779 -
Journal of Clinical Medicine Apr 2024Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that... (Review)
Review
Drusen are one of the most characteristic pathologies of precursor lesion of age-related macular degeneration (AMD). Drusen comprise a yellowish white substance that accumulates typically under the retinal pigment epithelium (RPE), and their constituents are lipids, complement, amyloid, crystallin, and others. In the past, many researchers have focused on drusen and tried to elucidate the pathophysiology of AMD because they believed that disease progression from early AMD to advanced AMD might be based on drusen or drusen might cause AMD. In fact, it is well established that drusen are the hallmark of precursor lesion of AMD and a major risk factor for AMD progression mainly based on their size and number. However, the existence of advanced AMD without drusen has long been recognized. For example, polypoidal choroidal vasculopathy (PCV), which comprises the majority of AMD cases in Asians, often lacks drusen. Thus, there is the possibility that drusen might be no more than a biomarker of AMD and not a cause of AMD. Now is the time to reconsider the relationship between AMD and drusen. In this review, we focus on early AMD pathogenesis based on basic research from the perspective of cholesterol metabolism and hypoxic response in the retina, and we discuss the role of drusen.
PubMed: 38731137
DOI: 10.3390/jcm13092608 -
European Journal of Ophthalmology May 2024To quantify and compare the different prevalence rates of specific retinal imaging biomarkers in patients with intermediate AMD (iAMD) and advanced non-neovascular AMD...
Differences in imaging biomarkers between patients with intermediate and advanced non-neovascular age-related macular degeneration (AMD) in the University of Colorado AMD registry.
PURPOSE
To quantify and compare the different prevalence rates of specific retinal imaging biomarkers in patients with intermediate AMD (iAMD) and advanced non-neovascular AMD (nnAMD).
METHODS
Cross-sectional study of patients with iAMD and advanced nnAMD. Imaging studies were reviewed for qualitative imaging biomarkers. Choroidal thickness measurements were obtained subfoveally and in 1000 um and 2000 um intervals away from the fovea. The Chi-squared test and Fisher's exact test were used to compare rates of imaging biomarkers among the two cohorts. -value of <0.05 was considered significant.
RESULTS
376 eyes of 197 patients with iAMD and 187 eyes of 97 patients with advanced nnAMD were recruited. There were significantly lower rates of the following imaging biomarkers in the iAMD compared with the advanced nnAMD cohorts: soft drusen (66.0% vs. 84.2%, = 0.001), calcified drusen (4.3% vs. 40.0%, < 0.0001), RPD (26.2% vs. 53.3%, < 0.0001), ORT (0.5% vs. 46.9%, < 0.0001), RP (1.1% vs. 46.3%, < 0.0001), pigment migration (53.2% vs. 100%, < 0.0001), and iRORA (17.9% vs. 80.2%, < 0.0001). In the iAMD cohort, choroidal thickness was significantly greater at 188 µm (SD: 60) and 194 µm (SD: 69), compared to the advanced nnAMD with measurements of 153 µm (SD: 68), and 161 µm (SD: 76). This difference was statistically significant ( < 0.0001 and = 0.0002).
CONCLUSIONS
Our results highlight significant differences in imaging biomarkers between both cohorts. Key biomarkers, such as iRORA, RPD, pigment migration, and thinner choroidal thickness, were associated with advanced nnAMD. Identifying these biomarkers early may help target patients who could benefit from new treatments, potentially delaying vision loss.
PubMed: 38725183
DOI: 10.1177/11206721241255156 -
Investigative Ophthalmology & Visual... May 2024We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography... (Comparative Study)
Comparative Study
PURPOSE
We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort.
METHODS
Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups.
RESULTS
This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant.
CONCLUSIONS
With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Choroid; Cross-Sectional Studies; Macular Degeneration; Retinal Drusen; Retinal Photoreceptor Cell Outer Segment; Retinal Pigment Epithelium; Tomography, Optical Coherence; Visual Acuity
PubMed: 38717424
DOI: 10.1167/iovs.65.5.17 -
Disease Models & Mechanisms Apr 2024Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the...
Mechanical stimulation as a mimic of drusen formation in the eye increases the expression of angiogenic factors in retinal pigment epithelial (RPE) cells, but the underlying molecular mechanisms remain unclear. We investigated and characterized the effects of mechanical stimulation on the expression of angiogenic factors in RPE cells both in vitro and in a mouse model. Mechanical stimulation increased the expression of vascular endothelial growth factor (VEGF, encoded by VEGFA) and other angiogenesis-related genes in cultured RPE1 cells. The presence of hypoxia-inducible factor 1α (HIF-1α, encoded by HIF1A) was also increased, and both knockdown of HIF-1α and treatment with the HIF-1α inhibitor CAY10585 attenuated the effect of mechanical stimulation on angiogenesis factor gene expression. Signaling by the tyrosine kinase SRC and p38 mitogen-activated protein kinase was involved in HIF-1α activation and consequent angiogenesis-related gene expression induced by mechanical stimulation. Our results suggest that SRC-p38 and HIF-1α signaling are involved in the upregulation of angiogenic factors in RPE cells by mechanical stimulation. Such in vivo suppression of upregulated expression of angiogenesis-related genes by pharmacological inhibitors of HIF-1α suggests a new potential approach to the treatment of age-related macular degeneration.
Topics: Retinal Pigment Epithelium; Hypoxia-Inducible Factor 1, alpha Subunit; Animals; Up-Regulation; p38 Mitogen-Activated Protein Kinases; Mice, Inbred C57BL; src-Family Kinases; Vascular Endothelial Growth Factor A; Stress, Mechanical; Signal Transduction; Mice; Cell Line; Angiogenesis Inducing Agents; Epithelial Cells; Humans
PubMed: 38691000
DOI: 10.1242/dmm.050640 -
Graefe's Archive For Clinical and... Apr 2024Geographic atrophy (GA) is an advanced, irreversible, and progressive form of age-related macular degeneration (AMD). Structural optical coherence tomography (OCT) and... (Review)
Review
BACKGROUND
Geographic atrophy (GA) is an advanced, irreversible, and progressive form of age-related macular degeneration (AMD). Structural optical coherence tomography (OCT) and OCT angiography (OCTA) have been largely used to characterize this stage of AMD and, more importantly, to define biomarkers associated with the development and progression of GA in AMD.
METHODS
Articles pertaining to OCT and OCTA biomarkers related to the development and progression of GA with relevant key words were used to search in PubMed, Researchgate, and Google Scholar. The articles were selected based on their relevance, reliability, publication year, published journal, and accessibility.
RESULTS
Previous reports have highlighted various OCT and OCTA biomarkers linked to the onset and advancement of GA. These biomarkers encompass characteristics such as the size, volume, and subtype of drusen, the presence of hyperreflective foci, basal laminar deposits, incomplete retinal pigment epithelium and outer retinal atrophy (iRORA), persistent choroidal hypertransmission defects, and the existence of subretinal drusenoid deposits (also referred to as reticular pseudodrusen). Moreover, biomarkers associated with the progression of GA include thinning of the outer retina, photoreceptor degradation, the distance between retinal pigment epithelium and Bruch's membrane, and choriocapillaris loss.
CONCLUSION
The advent of novel treatment strategies for GA underscores the heightened need for prompt diagnosis and precise monitoring of individuals with this condition. The utilization of structural OCT and OCTA becomes essential for identifying distinct biomarkers associated with the initiation and progression of GA.
PubMed: 38689123
DOI: 10.1007/s00417-024-06497-8