Retinal

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2019 Dec 2
The Western Eye Hospital, Imperial College Healthcare NHS Trust (ICHNT), London, UK
Retinal correlates of neurological disorders.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887800/

Abstract

Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.

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[Petr75]

2019 May 27
Expertisecentre Neuro-Ophthalmology, Departments of Neurology and Ophthalmology, Amsterdam UMC, Amsterdam, The Netherlands
Progression of Anterograde Trans-Synaptic Degeneration in the Human Retina Is Modulated by Axonal Convergence and Divergence
https://pubmed.ncbi.nlm.nih.gov/32165897/

Abstract

In the visual pathway of patients with multiple sclerosis (MS), the inner nuclear layer (INL) of the retina is a tight barrier for retrograde trans-synaptic degeneration. In this observational, retrospective cross-sectional study, segmented macular spectral domain optical coherence tomography (OCT) volume scans were reviewed to investigate if this observation also holds true for anterograde trans-synaptic degeneration. Significant thinning was found in all retinal layers in patients with outer retinal diseases compared with the healthy controls, while there was no significant attenuation of the outer retina in patients with MS. In contrast to the tight barrier function observed with retrograde trans-synaptic degeneration, the INL appears to be more permissive for the propagation of anterograde trans-synaptic degeneration. We speculate that this may be due to the size of the area affected and be explained by convergence and divergence of axons within the retinal layers. These findings are likely relevant to future restorative stem cell treatment of the outer retinal layers, as time may matter.

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2020 Mar 6
Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami
Targeted Kruppel-like Factor 4 Gene Knockout in Retinal Ganglion Cells Improves Visual Function in Multiple Sclerosis Mouse Model
https://pubmed.ncbi.nlm.nih.gov/32165410/

Abstract

Axonal demyelination injury and neuronal degeneration are the primary causes of visual disability in multiple sclerosis-linked optic neuritis (MS/optic neuritis) patients. Immunomodulatory therapies targeting inflammation have failed to avert the disease progression and no therapies exist to prevent the neuronal deficits seen in MS to date. Neuroprotective strategies targeting oligodendrocytes and astroglia have shown limited success due to a lack of axonal regeneration from injured neurons. In this study, we used the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS to investigate the axonal regenerative approach to improve the neuronal function. Our approach focused on targeted knockout of the developmentally regulated axon growth inhibitory Kruppel-like factor 4 (Klf4) gene in retinal ganglion cells (RGCs) of Klf4fl/fl mice by intravitreal delivery of AAV2-Cre-ires-EGFP recombinant virus 1) at the time of EAE sensitization, and 2) after the onset of optic neuritis-mediated visual defects in the mice. Klf4 gene knockout performed simultaneous with EAE sensitization prevented the visual loss as assessed by pattern electroretinograms (PERG) in the mice and protected the RGCs from EAE mediated death. More importantly, however, Klf4 gene knockout after the onset of optic neuritis also resulted in RGC neuroprotection with additional restoration of their function, thereby improving the visual function outcomes in the EAE model. This study establishes the efficacy of Klf4 targeted knockdown in EAE even after the onset of disease symptoms, and thus should be further explored as a potential treatment strategy for MS/Optic neuritis patients.Significance Statement Multiple sclerosis is a leading cause of permanent disability in young adults in which effective treatment has remained elusive. The neuroprotective strategies targeting oligodendrocytes and astroglia have shown limited success due to a lack of axonal regeneration from injured neurons. In the current study, we explored the axon regenerative approach to treat MS in mouse model and showed that targeted knockout of axon growth inhibitory Klf4 gene in RGCs of EAE mice is efficient in preventing not only the EAE mediated RGC death but also restoring the function of injured axons by facilitating regeneration, and thereby improving the visual function in the mice even after the onset of EAE mediated visual defects.

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2020 May 12.
Department of Neurology, Faculty of Medicine and Dentistry, University Hospital, Palacký University Olomouc, Olomouc, Czech Republic
Changes in Oxygen Saturation and the Retinal Nerve Fibre Layer in Patients With Optic Neuritis Associated With Multiple Sclerosis in a 6-month Follow-Up
https://pubmed.ncbi.nlm.nih.gov/32395882/

Abstract

Purpose: Optic neuritis (ON) is an inflammatory demyelinating disorder of the optic nerve, which can be the first manifestation of multiple sclerosis (MS). The main goal was to assess changes in the retinal nerve fibre layer (RNFL) and in retinal oxygen saturation [arterial (AS), venous (VS) and arterio-venous (A-V) difference] in the affected and unaffected eye.

Methods: Fifty patients with ON due to MS within 3 months of onset of symptoms were enrolled (17 males, mean age 35.3). All patients were examined at baseline (V1) and after 6 months (V2) using optical coherence tomography (OCT) to get RNFL values; automatic retinal oximetry to obtain saturation values; and ultrasound to exclude arterial stenosis, and orbital colour Doppler imaging was performed in the ophthalmic artery.

Results: At V1, AS was significantly increased in affected eye compared to unaffected eye (99.5% versus 98.0%, p = 0.03). Significant decrease in A-V difference from baseline was detected in both eyes for ON eye: 32.0% versus 29.0%, p = 0.004; for fellow eye: 31.4% versus 30.0%, p = 0.04. We did not observe any changes in retinal vessel diameter. There were no changes observed in blood flow in ophthalmic artery. At V1, there were no significant differences in RNFL, and significant loss of RNFL was confirmed in the affected eye at V2 (95 μm versus 86 μm, p = 0.0002) and in comparison with the fellow eye (86 μm versus 94 μm, p = 0.0002). There were no correlations between RNFL and saturation values at V1, although at V2, there was a negative correlation between the RNFL and AS (Spearman's rho = -0.480, p = 0.003) and between the RNFL and VS (rho = -0.620, p = 0.00007).

Conclusion: Retinal oximetry is altered in both eyes in MS patients with unilateral ON. During the course of the disease, the retinal oxygen consumption decreases to a different degree in each eye and this change is not completely followed by changes in the RNFL thickness, suggesting either sub-clinical ON or systemic effects in the clinically unaffected eye. Since this is the first and initial longitudinal evaluation of the saturation changes in MS patients, the clinical value of these findings needs to be deeper evaluated in the future studies.

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2020 Sep 3
The Tony and Leona Campane Center for Excellence in Image-guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases
https://pubmed.ncbi.nlm.nih.gov/32881874/


Abstract

Purpose: To investigate the association between outer retinal layer metrics, including photoreceptor outer segment volume, on spectral-domain optical coherence tomography (OCT) and brain volume on MRI in normal aging, Alzheimer's disease and Parkinson's disease.

Methods: This was an exploratory analysis of a cross-sectional cohort study that was approved by the Cleveland Clinic Institutional Review Board to evaluate neurodegenerative disorders. Subjects aged ≥ 50 were recruited. A comprehensive neurological exam, brain MRI with volumetric evaluation, and OCT were performed for each subject. Outer retinal layer parameters, including ellipsoid zone (EZ) to retinal pigment epithelium (RPE) volume (i.e., surrogate for panmacular photoreceptor outer segment volume), were evaluated with a novel OCT analysis platform.

Results: Of 85 subjects, 64 eyes of 64 subjects met MRI and OCT quality control criteria. Total brain volume (%ICV) significantly correlated with EZ-RPE volume in the normal cognition control group (n = 31, Pearson correlation coefficient 0.514, P < .01), the Parkinson's disease group (n = 19, Pearson correlation coefficient 0.482, P = .04), and the Alzheimer's dementia group (n = 14, Pearson correlation coefficient 0.526, P = .05). Multiple linear regression analysis revealed that photoreceptor outer segment (i.e., EZ-RPE) volume was an independent, influential factor on total brain volume in all study subjects (Coefficient 15.2, 95% confidence interval 7.8-22.6, P < .001).

Conclusion: Outer retinal parameters on OCT may serve as a novel biomarker related to brain volume. This correlation was noted in control subjects suggesting a possible developmental link between retina and brain volume. This relationship was also maintained with atrophic neurodegenerative disorders. Further research is needed to explore possible threshold differences for underlying neurodegenerative disorders.
Conflict of interest statement

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2020 Sep 29
Beijing Advanced Innovation Center for Intelligent Robots and Systems, Beijing Institute of Technology, Beijing, China
Effects of Retinal Transcription Regulation After GB20 Needling Treatment in Retina With Optic Neuritis
https://pubmed.ncbi.nlm.nih.gov/33117136/

Abstract

Optic neuritis (ON) is one of the most frequent symptoms of multiple sclerosis (MS) that results in progressive loss of axons and neurons. In clinical trials of Traditional Chinese Medicine, needling at the GB20 acupoint has been widely used for the treatment of ocular diseases, including ON. However, the molecular mechanisms of needling at this site are still unclear. In this study, we generated an experimental autoimmune encephalomyelitis (EAE) mouse model and investigated the effects of needling treatment at the GB20 acupoint on retina with EAE-associated ON. RNA sequencing of the retinal transcriptome revealed that, of the 234 differentially expressed genes induced by ON, 100 genes were upregulated, and 134 genes were downregulated by ON, while needling at the GB20 acupoint specifically reversed the expression of 21 genes compared with control treatment at GV16 acupoint. Among the reversed genes, Nr4a3, Sncg, Uchl1, and Tppp3 were involved in axon development and regeneration and were downregulated by ON, indicating the beneficial effect of needling at GB20. Further gene ontology (GO) enrichment analysis revealed that needling at GB20 affected the molecular process of Circadian rhythm in mouse retina with ON. Our study first reported that needling treatment after ON at the GB20 acupoint regulated gene expression of the retina and reversed the expression of downregulated axon development-related genes. This study also demonstrated that GV16 was a perfect control treatment site for GB20 in animal research. Our study provided a scientific basis for needling treatments at GB20 for ocular diseases.

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2020 Oct 29
Department of Neurology, Medical University of Vienna, Vienna, Austria
Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis
https://pubmed.ncbi.nlm.nih.gov/33194221/


Abstract

Background: PIRA (progression independent of relapse) has emerged as a term to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes in multiple sclerosis (MS).

Objective: To determine the impact of PIRA on retinal thinning, a biomarker of neuroaxonal degeneration in MS, in comparison to traditional disability worsening and relapse.

Methods: In a 4-year, prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular ganglion-cell-and-inner-plexiform-layer (GCIPL) and peripapillary-retinal-nerve-fibre-layer (pRNFL). PIRA was defined as an expanded disability status scale (EDSS) or symbol digit modalities test (SDMT) worsening confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening.

Results: Each PIRA event was associated with a mean additional loss of GCIPL (1.8 µm) and pRNFL (1.9 µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3 µm) and pRNFL (1.4 µm).

Conclusions: PIRA is associated with retinal thinning, likely reflecting neurodegenerative processes, not directly associated with focal inflammation. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.

[Petr75]

2020 Nov 30
Moorfields Eye Hospital and The National Hospital for Neurology and Neurosurgery, London, UK
Retinal asymmetry in multiple sclerosis
https://pubmed.ncbi.nlm.nih.gov/33253371/

Abstract

The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229-0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67-0.76) and IEAD (0.71, 95% CI 0.67-0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59-0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58-0.68, P < 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54-0.63, P < 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50-0.59, P < 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.

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2021 May 3
Center of Neuroimmunology, Institut d'Investigacions Biomediques August Pi Sunyer, Barcelona, Spain
In Vivo Molecular Changes in the Retina of Patients With Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/33974046/


Abstract

Purpose: Raman spectroscopy allows molecular changes to be quantified in vivo from the tissues like the retina. Here we aimed to assess the metabolic changes in the retina of patients with multiple sclerosis (MS).

Methods: We built a Raman spectroscopy prototype by connecting a scanning laser ophthalmoscope to a spectrophotometer. We defined the spectra of 10 molecules participating on energy supply, axon biology, or synaptic damage, which have been shown to be altered in the brain of patients with MS: cytochrome C, flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NADH), N-acetyl-aspartate (NAA), excitotoxicity, glutamate, amyloid β (Aβ), τ and α-synuclein (SNCA), phosphatidyl-ethanolamine, and phosphatidyl-choline. We studied these molecules in a prospective cohort of patients with MS, either in the chronic phase or during relapses of acute optic neuritis (AON).

Results: Significant changes to all these molecules were associated with age in healthy individuals. There was a significant decrease in NADH and a trend toward a decrease in NAA in patients with MS, as well as an increase in Aβ compared with healthy controls. Moreover, NADH and FAD increased over time in a longitudinal analysis of patients with MS, whereas Aβ diminished. In patients with acute retinal inflammation due to AON, there was a significant increase in FAD and a decrease in SNCA in the affected retina. Moreover, glutamate levels increased in the affected eyes after a 6-month follow-up.

Conclusions: Alterations of molecules related to axonal degeneration are observed during neuroinflammation and show dynamic changes over time, suggesting progressive neurodegeneration.