Browsing by Author "Harris, Alon"

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    Alzheimer's disease and primary open‐angle glaucoma associated with vascular health in patients of African descent
    (Wiley, 2018-12) Hutchins, Katherine; Harris, Alon; Thomas, Joseph; Alkhairy, Sameerah; Vercellin, Alice Chandra Verticchio; Shah, Aaditya; Siesky, Brent; Ophthalmology, School of Medicine
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    Artificial Intelligence to Aid Glaucoma Diagnosis and Monitoring: State of the Art and New Directions
    (MDPI, 2022) Nunez, Roberto; Harris, Alon; Ibrahim, Omar; Keller, James; Wikle, Christopher K.; Robinson, Erin; Zukerman, Ryan; Siesky, Brent; Verticchio, Alice; Rowe, Lucas; Guidoboni, Giovanna; Ophthalmology, School of Medicine
    Recent developments in the use of artificial intelligence in the diagnosis and monitoring of glaucoma are discussed. To set the context and fix terminology, a brief historic overview of artificial intelligence is provided, along with some fundamentals of statistical modeling. Next, recent applications of artificial intelligence techniques in glaucoma diagnosis and the monitoring of glaucoma progression are reviewed, including the classification of visual field images and the detection of glaucomatous change in retinal nerve fiber layer thickness. Current challenges in the direct application of artificial intelligence to further our understating of this disease are also outlined. The article also discusses how the combined use of mathematical modeling and artificial intelligence may help to address these challenges, along with stronger communication between data scientists and clinicians.
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    Asian Race and Primary Open-Angle Glaucoma: Where Do We Stand?
    (MDPI, 2022-04-28) Belamkar, Aditya; Harris, Alon; Oddone, Francesco; Verticchio Vercellin, Alice; Fabczak-Kubicka, Anna; Siesky, Brent; Ophthalmology, School of Medicine
    Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by irreversible retinal ganglion cell damage and visual field loss. The global POAG prevalence is estimated to be 3.05%, and near term is expected to significantly rise, especially within aging Asian populations. Primary angle-closure glaucoma disproportionately affects Asians, with up to four times greater prevalence of normal-tension glaucoma reported compared with high-tension glaucoma. Estimates for overall POAG prevalence in Asian populations vary, with Chinese and Indian populations representing the majority of future cases. Structural characteristics associated with glaucoma progression including the optic nerve head, retina, and cornea are distinct in Asians, serving as intermediates between African and European descent populations. Patterns in IOP suggest some similarities between races, with a significant inverse relationship between age and IOP only in Asian populations. Genetic differences have been suggested to play a role in these differences, however, a clear genetic pattern is yet to be established. POAG pathogenesis differs between Asians and other ethnicities, and it may differ within the broad classification of the Asian race. Greater awareness and further research are needed to improve treatment plans and outcomes for the increasingly high prevalence of normal tension glaucoma within aging Asian populations.
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    Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer’s Disease
    (IOS Press, 2023) Mathew, Sunu; WuDunn, Darrell; Mackay, Devin D.; Vosmeier, Aaron; Tallman, Eileen F.; Deardorff, Rachael; Harris, Alon; Farlow, Martin R.; Brosch, Jared R.; Gao, Sujuan; Apostolova, Liana G.; Saykin, Andrew J.; Risacher, Shannon L.; Radiology and Imaging Sciences, School of Medicine
    Background: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.
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    Baseline structural characteristics of the optic nerve head and retinal nerve fiber layer are associated with progressive visual field loss in patients with open-angle glaucoma
    (Public Library of Science, 2020-08-20) Siesky, Brent; Wentz, Scott M.; Januleviciene, Ingrida; Kim, Daniel H.; Burgett, Kendall M.; Vercellin, Alice C. Verticchio; Rowe, Lucas W.; Eckert, George J.; Harris, Alon; Biostatistics, School of Public Health
    Aims To examine the relationship between baseline structural characteristics of the optic nerve head (ONH) and retinal nerve fiber layer (RNFL) and functional disease progression in patients with open-angle glaucoma (OAG) over 5 years. Methods 112 OAG patients were prospectively examined at baseline and every 6 months over a period of five years. Structural glaucomatous changes were examined with optical coherence tomography (OCT) and Heidelberg retinal tomography-III (HRT-III), and functional disease progression with automated perimetry (Humphrey visual fields). Cox proportional hazard models were used to assess the relationship between baseline structural measurements and functional disease progression. Results From baseline over a 5-year period, statistically significant increases were found in OCT disc (D) area (p<0.001), cup (C) area (p<0.001), C/D area ratio (p<0.001), C/D horizontal ratio (p<0.001), C/D vertical ratio (p = 0.018), and a decrease in superior RNFL thickness (p = 0.008). Statistically significant increases were found in HRT-III C volume (p = 0.021), C/D area ratio (p = 0.046), mean C depth (p = 0.036), C shape (p = 0.008), and height variation contour (p = 0.020). Functional disease progression was detected in 37 of the 112 patients (26 of European descent and 11 of African descent; 33%). A statistically significant shorter time to functional progression was seen in patients with larger baseline OCT D area (p = 0.008), C area (p = 0.003), thicker temporal RNFL (p = 0.003), and in patients with a larger HRT-III C area (p = 0.004), C/D area ratio (p = 0.004), linear C/D ratio (p = 0.007), C shape (p = 0.032), or smaller rim area (p = 0.039), rim volume (p = 0.005), height variation contour (p = 0.041), mean RNFL thickness (p<0.001), or RNFL cross-sectional area (p = 0.002). Conclusion Baseline ONH and RNFL structural characteristics were associated with a significantly shorter time to functional glaucomatous progression and visual field loss through the five-year period in OAG patients.
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    Biofluid modeling of the coupled eye-brain system and insights into simulated microgravity conditions
    (PLOS, 2019-08-14) Salerni, Fabrizia; Repetto, Rodolfo; Harris, Alon; Pinsky, Peter; Prud'homme, Christophe; Szopos, Marcela; Guidoboni, Giovanna; Ophthalmology, School of Medicine
    This work aims at investigating the interactions between the flow of fluids in the eyes and the brain and their potential implications in structural and functional changes in the eyes of astronauts, a condition also known as spaceflight associated neuro-ocular syndrome (SANS). To this end, we propose a reduced (0-dimensional) mathematical model of fluid flow in the eyes and brain, which is embedded into a simplified whole-body circulation model. In particular, the model accounts for: (i) the flows of blood and aqueous humor in the eyes; (ii) the flows of blood, cerebrospinal fluid and interstitial fluid in the brain; and (iii) their interactions. The model is used to simulate variations in intraocular pressure, intracranial pressure and blood flow due to microgravity conditions, which are thought to be critical factors in SANS. Specifically, the model predicts that both intracranial and intraocular pressures increase in microgravity, even though their respective trends may be different. In such conditions, ocular blood flow is predicted to decrease in the choroid and ciliary body circulations, whereas retinal circulation is found to be less susceptible to microgravity-induced alterations, owing to a purely mechanical component in perfusion control associated with the venous segments. These findings indicate that the particular anatomical architecture of venous drainage in the retina may be one of the reasons why most of the SANS alterations are not observed in the retina but, rather, in other vascular beds, particularly the choroid. Thus, clinical assessment of ocular venous function may be considered as a determinant SANS factor, for which astronauts could be screened on earth and in-flight.
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    Blood circulation and aqueous humor flow in the eye : multi-scale modeling and clinical applications
    (2016-06-14) Cassani, Simone; Guidoboni, Giovanna; Arciero, Julia Concetta; Harris, Alon
    Glaucoma is a multi-factorial ocular disease associated with death of retinal ganglion cells and irreversible vision loss. Many risk factors contribute to glaucomatous damage, including elevated intraocular pressure (IOP), age, genetics, and other diseases such as diabetes and systemic hypertension. Interestingly, alterations in retinal hemodynamics have also been associated with glaucoma. A better understanding of the factors that contribute to these hemodynamic alterations could lead to improved and more appropriate clinical approaches to manage and hopefully treat glaucoma patients. In this thesis, we develop several mathematical models aimed at describing ocular hemodynamics and oxygenation in health and disease. Precisely we describe: (i) a time-dependent mathematical model for the retinal circulation that includes macrocirculation, microcirculation, phenomenological vascular regulation, and the mechanical effect of IOP on the retinal vasculature; (ii) a steady-state mathematical model for the retinal circulation that includes macrocirculation, microcirculation, mechanistic vascular regulation, the effect of IOP on the central retinal artery and central retinal vein, and the transport of oxygen in the retinal tissue using a Krogh cylinder type model; (iii) a steady-state mathematical model for the transport of oxygen in the retinal microcirculation and tissue based on a realistic retinal anatomy; and (iv) a steady-state mathematical model for the production and drainage of aqueous humor (AH). The main objective of this work is to study the relationship between IOP, systemic blood pressure, and the functionality of vascular autoregulation; the transport and exchange of oxygen in the retinal vasculature and tissue; and the production and drainage of AH, that contributes to the level of IOP. The models developed in this thesis predict that (i) the autoregulation plateau occurs for different values of IOP in hypertensive and normotensive patients. Thus, the level of blood pressure and functionality of autoregulation affect the changes in retinal hemodynamics caused by IOP and might explain the inconsistent outcomes of clinical studies; (ii) the metabolic and carbon dioxide mechanisms play a major role in the vascular regulation of the retina. Thus, the impairment of either of these mechanisms could cause ischemic damage to the retinal tissue; (iii) the multi-layer description of transport of oxygen in the retinal tissue accounts for the effect of the inner and outer retina, thereby improving the predictive ability of the model; (iv) a greater reduction in IOP is obtained if topical medications target AH production rather that AH drainage and if IOP-lowering medications are administrated to patients that exhibit a high initial level of IOP. Thus, the effectiveness of IOP-lowering medications depend on a patient’s value of IOP. In conclusion, the results of this thesis demonstrate that the insight provided by mathematical modeling alongside clinical studies can improve the understanding of diseases and potentially contribute to the clinical development of new treatments.
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    Blood flow regulation and oxygen transport in a heterogeneous model of the mouse retina
    (Elsevier, 2020-11) Fry, Brendan C.; Harris, Alon; Siesky, Brent; Arciero, Julia; Mathematical Sciences, School of Science
    Elevated intraocular pressure is the primary risk factor for glaucoma, yet vascular health and ocular hemodynamics have also been established as important risk factors for the disease. The precise physiological mechanisms and processes by which flow impairment and reduced tissue oxygenation relate to retinal ganglion cell death are not fully known. Mathematical modeling has emerged as a useful tool to help decipher the role of hemodynamic alterations in glaucoma. Several previous models of the retinal microvasculature and tissue have investigated the individual impact of spatial heterogeneity, flow regulation, and oxygen transport on the system. This study combines all three of these components into a heterogeneous mathematical model of retinal arterioles that includes oxygen transport and acute flow regulation in response to changes in pressure, shear stress, and oxygen demand. The metabolic signal (Si) is implemented as a wall-derived signal that reflects the oxygen deficit along the network, and three cases of conduction are considered: no conduction, a constant signal, and a flow-weighted signal. The model shows that the heterogeneity of the downstream signal serves to regulate flow better than a constant conducted response. In fact, the increases in average tissue PO2 due to a flow-weighted signal are often more significant than if the entire level of signal is increased. Such theoretical work supports the importance of the non-uniform structure of the retinal vasculature when assessing the capability and/or dysfunction of blood flow regulation in the retinal microcirculation.
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    Can the Treatment of Normal-Pressure Hydrocephalus Induce Normal-Tension Glaucoma? A Narrative Review of a Current Knowledge
    (MDPI, 2021-03) Hamarat, Yasin; Bartusis, Laimonas; Deimantavicius, Mantas; Lucinskas, Paulius; Siaudvytyte, Lina; Zakelis, Rolandas; Harris, Alon; Mathew, Sunu; Siesky, Brent; Janulevicienė, Ingrida; Ragauskas, Arminas; Radiology and Imaging Sciences, School of Medicine
    Ventriculoperitoneal shunt placement is the most commonly used treatment of normal-pressure hydrocephalus (NPH). It has been hypothesized that normal-tension glaucoma (NTG) is caused by the treatment of NPH by using the shunt to reduce intracranial pressure (ICP). The aim of this study is to review the literature published regarding this hypothesis and to emphasize the need for neuro-ophthalmic follow-up for the concerned patients. The source literature was selected from the results of an online PubMed search, using the keywords "hydrocephalus glaucoma" and "normal-tension glaucoma shunt". One prospective study on adults, one prospective study on children, two retrospective studies on adults and children, two case reports, three review papers including medical hypotheses, and one prospective study on monkeys were identified. Hypothesis about the association between the treatment of NPH using the shunt to reduce ICP and the development of NTG were supported in all reviewed papers. This suggests that a safe lower limit of ICP for neurological patients, especially shunt-treated NPH patients, should be kept. Thus, we proposed to modify the paradigm of safe upper ICP threshold recommended in neurosurgery and neurology into the paradigm of safe ICP corridor applicable in neurology and ophthalmology, especially for shunt-treated hydrocephalic and glaucoma patients.
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    Choroidal Thickness and Primary Open-Angle Glaucoma—A Narrative Review
    (MDPI, 2022-02-23) Verticchio Vercellin, Alice; Harris, Alon; Stone, Ari M.; Oddone, Francesco; Mendoza, Kristen Ann; Siesky, Brent; Ophthalmology, School of Medicine
    The choroid provides the majority of blood flow to the ocular tissues and structures that facilitate the processes of retinal metabolism responsible for vision. Specifically, the choriocapillaris provides a structural network of small blood vessels that supplies the retinal ganglion cells and deep ocular tissues. Similar to retinal nerve fiber layer thickness, choroidal thickness (CT) has been suggested to represent a quantifiable health biomarker for choroidal tissues. Glaucoma is a disease with vascular contributions in its onset and progression. Despite its importance in maintaining ocular structure and vascular functionality, clinical assessments of choroidal tissues have been historically challenged by the inaccessibility of CT biomarker targets. The development of optical coherence tomography angiography and enhanced depth imaging created a framework for assessing CT and investigating its relationship to glaucomatous optic neuropathy onset and progression. Pilot studies on CT in glaucoma are conflicting—with those both in support of, and against, its clinical utility. Complicating the data are highly customized analysis methods, small sample sizes, heterogeneous patient groups, and a lack of properly designed controlled studies with CT as a primary outcome. Herein, we review the available data on CT and critically discuss its potential relevance and limitations in glaucoma disease management.