Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Tribble, James R.; Hui, Flora; Quintero, Heberto; Hajji, Sana El; Bell, Katharina; Polo, Adriana Di; Williams, Pete A.

doi:10.1016/j.mam.2023.101193

Cited by 32 publications

(18 citation statements)

References 314 publications

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“…Inherited optic neuropathies such as Leber hereditary optic neuropathy and autosomal dominant optic atrophy are driven by whole-body mutations to mitochondrial proteins, yet typically present with a retinal ganglion cell-only phenotype. In glaucoma, a neurodegenerative disease characterized by the death of retinal ganglion cells, mitochondrial and metabolic dysfunction are also key pathogenic mechanisms [ 56 ]. The high frequency of mitochondrial Complex I mutations [ 1 ], variation in mitochondrial transcription factor A [ 1 ] and thinning of the ganglion cell layers in Parkinson’s disease patients [ 8 , 37 , 21 , 63 ] are suggestive of the potential for retinal ganglion cell loss in Parkinson’s disease.…”

Section: Discussionmentioning

confidence: 99%

“…As retinal ganglion cells are vulnerable to metabolic stress and treatments targeting these processes are neuroprotective [ 56 ], we next assessed whether administration of NAM (the amide of vitamin B 3 and a precursor to the essential metabolite nicotinamide adenine dinucleotide (NAD), via drinking water accessible) could provide neuroprotection for dopaminergic amacrine cells in this intravitreal MPTP model. Metabolic dysfunction has gained increasing attention in the disease pathology of Parkinson’s disease and other common neurodegenerative diseases [ 45 ] with NAD deficiency frequently detected [ 64 , 65 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

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Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Rombaut,

Jovancevic,

Wong

et al. 2024

acta neuropathol commun

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Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Studies have demonstrated that the retina in patients with Parkinson’s disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson’s disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells—a sensitive neuron in the retina—at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson’s disease and retinal ganglion cell injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Rombaut,

Jovancevic,

Wong

et al. 2024

acta neuropathol commun

Self Cite

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“…A recent study assessed the influence of 22 genetic variants predisposing to POAG with visual field loss in Japanese patients (n = 426) and control subjects (n = 246), classifying the genotypes into those associated with IOP elevation or with optic nerve vulnerability independent of IOP and assessing indicators of the severity of visual field loss [ 77 ]. Therefore, the effect of better response can be due to the baseline difference in IOP caused by the SNP, but the effect of the genotype on all the novel aspects of neuroprotection [ 78 ] and on visual loss in the long-term deserves deeper investigation in well-designed studies with homogeneous outcome measures. Furthermore, more clinical trials are needed assessing both the effect of altered metabolism due to genetic variants, but also how safety can be affected by SNPs of genes encoding for proteins involved in pathophysiology of POAG but that can be associated to off target phenomena in other districts.…”

Section: Discussionmentioning

confidence: 99%

Effect of genotype on individual response to the pharmacological treatment of glaucoma: a systematic review and meta-analysis

Scuteri,

Pocobelli,

Sakurada

et al. 2023

Biol Direct

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The social impact of glaucoma is worth of note: primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness worldwide, affecting some 68.56 million people with overall prevalence of 2.4%. Since one of the main risk factors for the development of POAG is the increase of intraocular pressure (IOP) causing retinal ganglion cells death, the medical treatment of POAG consists in the use of drugs endowed with neuroprotective effect and able to reduce IOP. These drugs include beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors, alpha or cholinergic agonists and rho kinase inhibitors. However, not all the patients respond to the same extent to the therapy in terms of efficacy and safety. Genetics and genome wide association studies have highlighted the occurrence of mutations and polymorphisms influencing the predisposition to develop POAG and its phenotype, as well as affecting the response to pharmacological treatment. The present systematic review and meta-analysis aims at identifying genetic variants and at verifying whether these can influence the responsiveness of patients to therapy for efficacy and safety. It follows the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 recommendations. The literature search was conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science and Public Health Genomics and Precision Health Knowledge Base up to June 14th, 2023. The search retrieved 1026 total records, among which eight met the eligibility criteria for inclusion in the analysis. The results demonstrated that the most investigated pharmacogenetic associations concern latanoprost and timolol, and that efficacy was studied more in depth than safety. Moreover, the heterogeneity of design and paucity of studies prompt further investigation in randomized clinical trials. In fact, adequately powered and designed pharmacogenetic association studies are needed to provide body of evidence with good certainty for a more appropriate use of medical therapy in POAG.PROSPERO registration: CRD42023434867.

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“…Our findings demonstrate that the 2D-CNN algorithm consistently provided robust results compared to their 3D counterparts tested in this study for glaucoma detection, achieving AUC values of 0.960 and 0.943 for the macular and ONH OCT test images, respectively. Given the scarcity of pre-trained 3D models trained on extensive datasets, this comparative analysis underscores the overall utility of 2D and 3D-CNN algorithms in advancing glaucoma diagnostic systems in ophthalmology and highlights the potential of 2D algorithms for volumetric OCT image-based glaucoma detection.Glaucoma, a neurodegenerative disease affecting nearly 80 million people globally 1 , is characterized by the progressive degeneration of retinal ganglion cells, leading to vision impairment [1][2][3][4][5] . It stands as a leading contributor to irreversible vision loss, often going undetected until considerable damage has occurred [6][7][8] .…”

mentioning

confidence: 99%

“…Glaucoma, a neurodegenerative disease affecting nearly 80 million people globally 1 , is characterized by the progressive degeneration of retinal ganglion cells, leading to vision impairment [1][2][3][4][5] . It stands as a leading contributor to irreversible vision loss, often going undetected until considerable damage has occurred [6][7][8] .…”

mentioning

confidence: 99%

Assessing the efficacy of 2D and 3D CNN algorithms in OCT-based glaucoma detection

Rasel,

Wu,

Chiariglione

et al. 2024

Sci Rep

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Glaucoma is a progressive neurodegenerative disease characterized by the gradual degeneration of retinal ganglion cells, leading to irreversible blindness worldwide. Therefore, timely and accurate diagnosis of glaucoma is crucial, enabling early intervention and facilitating effective disease management to mitigate further vision deterioration. The advent of optical coherence tomography (OCT) has marked a transformative era in ophthalmology, offering detailed visualization of the macula and optic nerve head (ONH) regions. In recent years, both 2D and 3D convolutional neural network (CNN) algorithms have been applied to OCT image analysis. While 2D CNNs rely on post-prediction aggregation of all B-scans within OCT volumes, 3D CNNs allow for direct glaucoma prediction from the OCT data. However, in the absence of extensively pre-trained 3D models, the comparative efficacy of 2D and 3D-CNN algorithms in detecting glaucoma from volumetric OCT images remains unclear. Therefore, this study explores the efficacy of glaucoma detection through volumetric OCT images using select state-of-the-art (SOTA) 2D-CNN models, 3D adaptations of these 2D-CNN models with specific weight transfer techniques, and a custom 5-layer 3D-CNN-Encoder algorithm. The performance across two distinct datasets is evaluated, each focusing on the macula and the ONH, to provide a comprehensive understanding of the models’ capabilities in identifying glaucoma. Our findings demonstrate that the 2D-CNN algorithm consistently provided robust results compared to their 3D counterparts tested in this study for glaucoma detection, achieving AUC values of 0.960 and 0.943 for the macular and ONH OCT test images, respectively. Given the scarcity of pre-trained 3D models trained on extensive datasets, this comparative analysis underscores the overall utility of 2D and 3D-CNN algorithms in advancing glaucoma diagnostic systems in ophthalmology and highlights the potential of 2D algorithms for volumetric OCT image-based glaucoma detection.

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Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Cited by 32 publications

References 314 publications

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Effect of genotype on individual response to the pharmacological treatment of glaucoma: a systematic review and meta-analysis

Assessing the efficacy of 2D and 3D CNN algorithms in OCT-based glaucoma detection

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