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Yang Y, Qin B, Ng TK, Sun X, Cao W, Chen Y. Serum lipid and lipoprotein profiles and their association with intraocular pressure in primary open-angle glaucoma: an observational cross-sectional study in the Chinese population. Lipids Health Dis 2024; 23:323. [PMID: 39350087 PMCID: PMC11441088 DOI: 10.1186/s12944-024-02316-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Glaucoma is a leading cause of vision impairment and permanent blindness. Primary open-angle glaucoma (POAG) is a prominent type of primary glaucoma; however, its cause is difficult to determine. This study aimed to analyze the serum lipid profile of Chinese POAG patients and assess its correlation with intraocular pressure (IOP). METHODS The study included 1,139, 1,248, and 356 Chinese individuals with POAG, primary angle closure glaucoma (PACG), and controls, respectively. Peripheral whole blood samples were collected at the time of diagnosis. Enzymatic colorimetry was used to determine serum levels of different lipids: high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, cholesterol, and very low-density lipoproteins (VLDL). Additionally, immunoturbidimetry was used to quantify serum levels of apolipoproteins A (APOA), B (APOB), E (APOE), and lipoprotein A [Lp(a)], while intraocular pressure (IOP) was measured in all patients with POAG. RESULTS After adjusting for age and sex, patients with POAG exhibited elevated serum levels of VLDL, APOA, and APOE but mitigated cholesterol levels compared with the control participants. Significantly lower serum triglyceride, VLDL, and Lp(a) levels were found in patients with PACG than in control participants. Serum cholesterol (P = 0.019; β = -0.75, 95% confidence interval [CI]: -1.38 - -0.12) and HDL levels (P < 0.001; β = -2.91, 95% CI: -4.58 - -1.25) were inversely linked to IOP in patients with POAG, after adjusting for age, sex, and ocular metrics. In addition, serum Lp(a) levels were correlated with the average IOP (P = 0.023; β = -0.0039, 95% CI: -0.0073 - -0.006) and night peak (P = 0.027; β = -0.0061, 95% CI: -0.0113 - -0.0008) in patients with POAG. CONCLUSIONS Significantly different serum lipid and lipoprotein profiles were observed in POAG and PACG patients. This study highlighted the differences in serum lipid and lipoprotein levels among Chinese POAG patients and their relationship with IOP and IOP fluctuation. Serum lipid and lipoprotein profiles should be considered while evaluating glaucoma risk.
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Affiliation(s)
- Yaping Yang
- Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China
- Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai, China
- Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Bo Qin
- Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China
- Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai, China
- Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
- Shanghai Aier Eye Hospital, Aier Eye Hospital Group Co. Ltd, Shanghai, China
| | - Tsz Kin Ng
- Joint Shantou International Eye Center of Shantou University, The Chinese University of Hong Kong, Shantou, Guangdong, China
- Shantou University Medical College, Shantou, Guangdong, China
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xinghuai Sun
- Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China
- Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai, China
- Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China
| | - Wenjun Cao
- Department of Clinical Laboratory, Eye and Ear Nose Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yuhong Chen
- Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.
- Key Laboratory of Myopia, Ministry of Health, Fudan University, Shanghai, China.
- Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China.
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Bathini P, Brai E, Balin BJ, Bimler L, Corry DB, Devanand DP, Doty RL, Ehrlich GD, Eimer WA, Fulop T, Hahn DL, Hammond CJ, Infanti J, Itzhaki R, Lathe R, Little CS, McLeod R, Moein ST, Nelson AR, Perry G, Shemesh OA, Tanzi RE, Webley WC, Schultek NM, Alberi Auber L. Sensory Dysfunction, Microbial Infections, and Host Responses in Alzheimer's Disease. J Infect Dis 2024; 230:S150-S164. [PMID: 39255393 DOI: 10.1093/infdis/jiae328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2024] Open
Abstract
Sensory functions of organs of the head and neck allow humans to interact with the environment and establish social bonds. With aging, smell, taste, vision, and hearing decline. Evidence suggests that accelerated impairment in sensory abilities can reflect a shift from healthy to pathological aging, including the development of Alzheimer's disease (AD) and other neurological disorders. While the drivers of early sensory alteration in AD are not elucidated, insults such as trauma and infections can affect sensory function. Herein, we review the involvement of the major head and neck sensory systems in AD, with emphasis on microbes exploiting sensory pathways to enter the brain (the "gateway" hypothesis) and the potential feedback loop by which sensory function may be impacted by central nervous system infection. We emphasize detection of sensory changes as first-line surveillance in senior adults to identify and remove potential insults, like microbial infections, that could precipitate brain pathology.
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Affiliation(s)
- Praveen Bathini
- Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
| | | | - Brian J Balin
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
| | - Lynn Bimler
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - David B Corry
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Department of Medicine, Dan L. Duncan Comprehensive Cancer Center, Biology of Inflammation Center, and the Michael E. DeBakey VA Center for Translational Research in Inflammatory Diseases, Baylor College of Medicine, Houston, Texas, USA
- Department of Pathology and Immunology, Dan L. Duncan Comprehensive Cancer Center, Biology of Inflammation Center, and the Michael E. DeBakey VA Center for Translational Research in Inflammatory Diseases, Baylor College of Medicine, Houston, Texas, USA
| | - Davangere P Devanand
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Department of Psychiatry and Neurology, Irving Medical Center, Columbia University, New York, USA
| | - Richard L Doty
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Smell and Taste Center, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Garth D Ehrlich
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Center for Genomic Sciences, Institute for Molecular Medicine and Infectious Disease, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - William A Eimer
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
- Harvard Medical School, Harvard University, Cambridge, Massachusetts, USA
| | - Tamas Fulop
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Department of Medicine, Division of Geriatrics, Faculty of Medicine and Health Sciences, Research Center on Aging, Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - David L Hahn
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
| | - Christine J Hammond
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Division of Research, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA
| | - Joseph Infanti
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Division of Research, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA
| | - Ruth Itzhaki
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Institute of Population Ageing, University of Oxford, Oxford, United Kingdom
| | - Richard Lathe
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Division of Infection Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom
| | - Christopher Scott Little
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Center for Chronic Disorders of Aging, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA
| | - Rima McLeod
- Departments of Ophthalmology and Visual Sciences, University of Chicago, Chicago, Illinois, USA
- Department of Pediatrics Infectious Diseases, University of Chicago, Chicago, Illinois, USA
| | - Shima T Moein
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Smell and Taste Center, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amy R Nelson
- Department of Physiology and Cell Biology, University of South Alabama, Mobile, Alabama, USA
| | - George Perry
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
- Department of Biology, The University of Texas at San Antonio, San Antonio, Texas, USA
| | - Or A Shemesh
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Rudolph E Tanzi
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA
- Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
- Harvard Medical School, Harvard University, Cambridge, Massachusetts, USA
| | - Wilmore C Webley
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
- Department of Microbiology, University of Massachusetts, Amherst, Massachusetts, USA
| | - Nikki M Schultek
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
| | - Lavinia Alberi Auber
- The Alzheimer's Pathobiome Initiative (AlzPI), Wake Forest, North Carolina, USA
- BrainFit4Life, Fribourg, Switzerland
- Intracell Research Group, LLC, Wake Forest, North Carolina, USA
- Department of Medicine, University of Fribourg, Fribourg, Switzerland
- VitalizeDx, Epalinges, Switzerland
- VitalizeDx Eu, Trieste, Italy
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Sampani K, Ness S, Tuz-Zahra F, Aytan N, Spurlock EE, Alluri S, Chen X, Siegel NH, Alosco ML, Xia W, Tripodis Y, Stein TD, Subramanian ML. Neurodegenerative biomarkers in different chambers of the eye relative to plasma: an agreement validation study. Alzheimers Res Ther 2024; 16:192. [PMID: 39187891 PMCID: PMC11346268 DOI: 10.1186/s13195-024-01556-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/11/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND Protein biomarkers have been broadly investigated in cerebrospinal fluid and blood for the detection of neurodegenerative diseases, yet a clinically useful diagnostic test to detect early, pre-symptomatic Alzheimer's disease (AD) remains elusive. We conducted this study to quantify Aβ40, Aβ42, total Tau (t-Tau), hyperphosphorylated Tau (ptau181), glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) in eye fluids relative to blood. METHODS In this cross-sectional study we collected vitreous humor, aqueous humor, tear fluid and plasma in patients undergoing surgery for eye disease. All six biomarkers were quantitatively measured by digital immunoassay. Spearman and Bland-Altman correlation analyses were performed to assess the agreement of levels between ocular fluids and plasma. RESULTS Seventy-nine adults underwent pars-plana vitrectomy in at least one eye. Of the 79, there were 77 vitreous, 67 blood, 56 tear fluid, and 51 aqueous samples. All six biomarkers were quantified in each bio-sample, except GFAP and NfL in tear fluid due to low sample volume. All six biomarkers were elevated in vitreous humor compared to plasma samples. T-Tau, ptau181, GFAP and NfL were higher in aqueous than in plasma, and t-Tau and ptau181 concentrations were higher in tear fluid than in plasma. Significant correlations were found between Aβ40 in plasma and tears (r = 0.5; p = 0.019), t-Tau in plasma and vitreous (r = 0.4; p = 0.004), NfL in plasma and vitreous (r = 0.3; p = 0.006) and plasma and aqueous (r = 0.5; p = 0.004). No significant associations were found for Aβ42, ptau181 and GFAP among ocular fluids relative to plasma. Bland-Altman analysis showed aqueous humor had the closest agreement to plasma across all biomarkers. Biomarker levels in ocular fluids revealed statistically significant associations between vitreous and aqueous for t-Tau (r = 0.5; p = 0.001), GFAP (r = 0.6; p < 0.001) and NfL (r = 0.7; p < 0.001). CONCLUSION AD biomarkers are detectable in greater quantities in eye fluids than in plasma and show correlations with levels in plasma. Future studies are needed to assess the utility of ocular fluid biomarkers as diagnostic and prognostic markers for AD, especially in those at risk with eye disease.
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Affiliation(s)
- Konstantina Sampani
- Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Steven Ness
- Department of Ophthalmology, Boston Medical Center, Boston, MA, 02118, USA
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Fatima Tuz-Zahra
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Nurgul Aytan
- Boston University Alzheimer's Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Elizabeth E Spurlock
- Boston University Alzheimer's Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Sreevardhan Alluri
- Department of Ophthalmology, Boston Medical Center, Boston, MA, 02118, USA
| | - Xuejing Chen
- Department of Ophthalmology, Boston Medical Center, Boston, MA, 02118, USA
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Nicole H Siegel
- Department of Ophthalmology, Boston Medical Center, Boston, MA, 02118, USA
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Michael L Alosco
- Boston University Alzheimer's Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Department of Psychology, University of Arizona, Tucson, AZ, USA
| | - Weiming Xia
- Department of Pharmacology and Experimental Therapeutics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Geriatric Research Education and Clinical Center, Bedford Veterans Affairs Medical Center, Bedford, MA, USA
| | - Yorghos Tripodis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Boston University Alzheimer's Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Thor D Stein
- Boston University Alzheimer's Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
- Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.
- Department of Veterans Affairs Medical Center, VA Boston Healthcare System, Boston, MA, USA.
- Department of Veterans Affairs Medical Center, VA Bedford Healthcare System, Bedford, MA, USA.
| | - Manju L Subramanian
- Department of Ophthalmology, Boston Medical Center, Boston, MA, 02118, USA.
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA.
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Mick P, Kabir R, Karunatilake M, Kathleen Pichora-Fuller M, Young TL, Sosero Y, Gan-Or Z, Wittich W, Phillips NA. APOE-ε4 is not associated with pure-tone hearing thresholds, visual acuity or cognition, cross-sectionally or over 3 years of follow up in the Canadian Longitudinal Study on Aging. Neurobiol Aging 2024; 138:72-82. [PMID: 38547662 DOI: 10.1016/j.neurobiolaging.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 01/15/2024] [Accepted: 01/16/2024] [Indexed: 04/09/2024]
Abstract
INTRODUCTION Hearing loss and diminished visual acuity are associated with poorer cognition, but the underlying mechanisms are not understood. The apolipoprotein (APOE) ε4 allelic variant may drive the associations. We tested whether APOE-ε4 allele count (0, 1, or 2) was associated with declines in memory, executive function, pure-tone hearing threshold averages, and pinhole-corrected visual acuity among participants in the Canadian Longitudinal Study on Aging (CLSA). METHODS Multivariable linear mixed regression models were utilized to assess associations between APOE-ε4 allele count and each of the outcome variables. For each main effects model, interactions between APOE-ε4 and sex and age group (45-54-, 55-64-, 65-74-, and 75-85 years) respectively, were analyzed. RESULTS Significant associations were not observed in main effects models. Models including APOE-ε4 * age (but not APOE-ε4 * sex) interaction terms better fit the data compared to main effects models. In age group-stratified models, however, there were minimal differences in effect estimates according to allele count. CONCLUSION APOE-ε4 allele count does not appear to be a common cause of sensory-cognitive associations in this large cohort.
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Affiliation(s)
- Paul Mick
- University of Saskatchewan, College of Medicine, Department of Surgery, Canada.
| | | | - Malshi Karunatilake
- University of Alberta, College of Health Sciences, Department of Ophthalmology and Visual Sciences, Canada
| | - M Kathleen Pichora-Fuller
- Professor emeritus, University of Toronto, Faculty of Arts and Sciencies, Department of Psychology, Canada
| | - Terry-Lyn Young
- Memorial University of Newfoundland, Faculty of Medicine, Canada
| | - Yuri Sosero
- McGill University, Faculty of Medicine and Health Sciences, Department of Human Genetics, Canada
| | - Ziv Gan-Or
- McGill University, Faculty of Medicine and Health Sciences, Department of Human Genetics, Canada
| | | | - Natalie A Phillips
- Concordia University, Faculty of Arts and Sciences, Department of Psychology, Canada
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Terhaar HM, Henriksen MDL, Mehaffy C, Hess A, McMullen RJ. The use of shotgun label-free quantitative proteomic mass spectrometry to evaluate the inflammatory response in aqueous humor from horses with uveitis compared to ophthalmologically healthy horses. Vet Ophthalmol 2024; 27:40-52. [PMID: 37144658 DOI: 10.1111/vop.13107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/06/2023]
Abstract
OBJECTIVE The objective of this study was to use shotgun label-free tandem mass spectrometry (LF-MS/MS) to evaluate aqueous humor (AH) from horses with uveitis (UH) compared to ophthalmologically healthy horses (HH). ANIMALS STUDIED Twelve horses diagnosed with uveitis based on ophthalmic examination and six ophthalmologically healthy horses (postmortem) purchased for teaching purposes. PROCEDURES All horses received a complete ophthalmic examination and physical exam. Aqueous paracentesis was performed on all horses and AH total protein concentrations were measured with nanodrop (TPn) and refractometry (TPr). AH samples were analyzed with shotgun LF-MS/MS and proteomic data were compared between groups using Wilcoxon rank-sum test. RESULTS A total of 147 proteins were detected, 11 proteins had higher abundance in UH, and 38 proteins had lower abundance in UH. Proteins with higher abundance included apolipoprotein E, alpha-2-macroglobulin (A2M), alpha-2-HS-glycoprotein, prothrombin, fibrinogen, complement component 4 (C4), joining chain for IgA and IgM, afamin, and amine oxidase. There were positive correlations between TPn (p = .003) and TPr (p = .0001) compared to flare scores. CONCLUSION Differential abundance of A2M, prothrombin, fibrinogen, and C4 indicate upregulation of the complement and coagulation cascade in equine uveitis. Proinflammatory cytokines and the complement cascade have potential as therapeutic targets for equine uveitis.
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Affiliation(s)
- Hannah M Terhaar
- Comparative Ophthalmology, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Michala de Linde Henriksen
- Comparative Ophthalmology, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Carolina Mehaffy
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Ann Hess
- Department of Statistics, College of Natural Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Richard J McMullen
- Equine Ophthalmology, Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, JT Vaughan Large Animal Teaching Hospital, Auburn, Alabama, USA
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Risk of dementia in newly diagnosed glaucoma: a nationwide cohort study in Korea. Ophthalmology 2023:S0161-6420(23)00128-8. [PMID: 36822436 DOI: 10.1016/j.ophtha.2023.02.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 02/23/2023] Open
Abstract
PURPOSE To investigate the risk of dementia in participants with newly diagnosed glaucoma. DESIGN A nationwide cohort study using authorized data provided by the Korean National Health Insurance Service (NHIS). PARTICIPANTS A total of 788,961 participants aged ≥ 45 years in 2006, who did not have dementia or glaucoma between 2002 and 2005, were included. METHODS Data were collected from a nationwide population-based retrospective cohort study using the Korean NHIS database. From January 2006 to December 2017, participants were tracked for the diagnosis of glaucoma or dementia using claims data. The prospective association between newly diagnosed glaucoma and the risk of dementia was investigated using a multivariable Cox proportional hazard model adjusted for age, sex, behavioral factors, and systemic and ocular comorbidities. MAIN OUTCOME MEASURES Hazard ratios and 95% confidence intervals for dementia development according to the parameters, including glaucoma diagnosis. RESULTS Overall, 7.0% of the participants developed dementia after an average of 7.4 years. A newly diagnosed glaucoma was associated with a higher risk of dementia (hazards ratio [HR] 1.89, 95% confidence interval [CI] 1.57 to 2.27) independent of age, sex, body mass index, income, smoking and drinking status, visual acuity, and other systemic comorbidities, such as diabetes, hypertension, stroke, and depression. An association between the risk of dementia and glaucoma was noted in participants with Alzheimer's disease (AD) but not in those with vascular dementia. The risk of dementia in relation to glaucoma was higher in older participants (HR = 3.15 (≥ 65 years) vs. 1.56 (< 65 years), P < 0.0001). CONCLUSION This nationwide cohort study found that individuals with newly diagnosed glaucoma were at a higher risk of developing dementia, particularly AD. This association was greater among older individuals in the studied population.
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Pitts KM, Neeson CE, Hall NE, Lin JB, Falah HK, Wang SL, Lo KT, Song CE, Margeta MA, Solá-Del Valle DA. Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma. Transl Vis Sci Technol 2022; 11:1. [DOI: 10.1167/tvst.11.11.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Kristen M. Pitts
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Cameron E. Neeson
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Nathan E. Hall
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Jonathan B. Lin
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Henisk K. Falah
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Silas L. Wang
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Kristine T. Lo
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Christian E. Song
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Milica A. Margeta
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - David A. Solá-Del Valle
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
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8
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Margeta MA, Yin Z, Madore C, Pitts KM, Letcher SM, Tang J, Jiang S, Gauthier CD, Silveira SR, Schroeder CM, Lad EM, Proia AD, Tanzi RE, Holtzman DM, Krasemann S, Chen DF, Butovsky O. Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. Immunity 2022; 55:1627-1644.e7. [PMID: 35977543 PMCID: PMC9488669 DOI: 10.1016/j.immuni.2022.07.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 05/09/2022] [Accepted: 07/18/2022] [Indexed: 12/27/2022]
Abstract
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.
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Affiliation(s)
- Milica A Margeta
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Zhuoran Yin
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Charlotte Madore
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France
| | - Kristen M Pitts
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Sophia M Letcher
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
| | - Jing Tang
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuhong Jiang
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Christian D Gauthier
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sebastian R Silveira
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Caitlin M Schroeder
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Eleonora M Lad
- Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA
| | - Alan D Proia
- Department of Pathology, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Campbell University School of Osteopathic Medicine, Lillington, NC, USA
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| | - David M Holtzman
- Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA
| | - Susanne Krasemann
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dong Feng Chen
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Oleg Butovsky
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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9
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Iridium nanoclusters as high sensitive-tunable elemental labels for immunoassays: Determination of IgE and APOE in aqueous humor by inductively coupled plasma-mass spectrometry. Talanta 2022; 244:123424. [DOI: 10.1016/j.talanta.2022.123424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/16/2022] [Accepted: 03/28/2022] [Indexed: 11/18/2022]
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10
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Michalke B. Review about Powerful Combinations of Advanced and Hyphenated Sample Introduction Techniques with Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) for Elucidating Trace Element Species in Pathologic Conditions on a Molecular Level. Int J Mol Sci 2022; 23:ijms23116109. [PMID: 35682788 PMCID: PMC9181184 DOI: 10.3390/ijms23116109] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
Element analysis in clinical or biological samples is important due to the essential role in clinical diagnostics, drug development, and drug-effect monitoring. Particularly, the specific forms of element binding, actual redox state, or their spatial distribution in tissue or in single cells are of interest in medical research. This review summarized exciting combinations of sophisticated sample delivery systems hyphenated to inductively coupled plasma-mass spectrometry (ICP-MS), enabling a broadening of information beyond the well-established outstanding detection capability. Deeper insights into pathological disease processes or intracellular distribution of active substances were provided, enabling a better understanding of biological processes and their dynamics. Examples were presented from spatial elemental mapping in tissue, cells, or spheroids, also considering elemental tagging. The use of natural or artificial tags for drug monitoring was shown. In the context of oxidative stress and ferroptosis iron, redox speciation gained importance. Quantification methods for Fe2+, Fe3+, and ferritin-bound iron were introduced. In Wilson’s disease, free and exchangeable copper play decisive roles; the respective paragraph provided information about hyphenated Cu speciation techniques, which provide their fast and reliable quantification. Finally, single cell ICP-MS provides highly valuable information on cell-to-cell variance, insights into uptake of metal-containing drugs, and their accumulation and release on the single-cell level.
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Affiliation(s)
- Bernhard Michalke
- Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München-German Research Center for Environmental Health GmbH, 85764 Neuherberg, Germany
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11
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Reinehr S, Mueller-Buehl AM, Tsai T, Joachim SC. Specific Biomarkers in the Aqueous Humour of Glaucoma Patients. Klin Monbl Augenheilkd 2022; 239:169-176. [PMID: 35211939 DOI: 10.1055/a-1690-7468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Glaucoma, a multifactorial neurodegenerative disease, is the second most common cause of blindness. Since early diagnosis facilitates timely treatment, it is therefore essential to identify appropriate markers. In the future, so-called biomarkers could be helpful in early detection and follow-up. In glaucoma, these parameters could be obtained in the aqueous humour. Altered antibodies, proteins, microRNA (miRNA) and trace element levels have already been identified. This review provides insight into possible changes in the aqueous humour of patients with primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) or pseudoexfoliation glaucoma (PEXG). Studies on antibody changes in POAG patients identified an upregulation of immune system associated antibodies such as heat shock protein (HSP) 27. HSP27 was also upregulated in PEXG patients but decreased in NTG. In POAG and PEXG samples, the levels of certain proteins, including interleukins and endothelin-1, were elevated. The vasoconstrictor endothelin-1 may play a role in regulating intraocular pressure. By contrast, proteins playing a role in the response to oxidative stress were downregulated. In NTG patients, proteins responsible for the elimination of toxic by-products from the respiratory chain were downregulated. In addition, the aqueous humour of POAG and PEXG patients contained several miRNAs that have been linked to tissue development, neurological disease and cellular organisation. Other miRNAs regulated in glaucoma play a role in extracellular matrix remodelling and thus may affect drainage resistance in the trabecular meshwork. It is also interesting to note that the aqueous humour of glaucoma patients showed changes in the levels of trace elements such as zinc and selenium. The elevated zinc levels could be responsible for the imbalance of intraocular matrix metalloproteinases and thus for increased intraocular pressure. All these studies demonstrate the complex changes in aqueous humour in glaucoma. Some of these biomarkers may be useful in the future for early diagnosis of the disease.
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Affiliation(s)
- Sabrina Reinehr
- Experimental Eye Research Institute, Ruhr-Universität Bochum, Deutschland
| | | | - Teresa Tsai
- Experimental Eye Research Institute, Ruhr-Universität Bochum, Deutschland
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12
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Ueda M. Transthyretin: Its function and amyloid formation. Neurochem Int 2022; 155:105313. [PMID: 35218869 DOI: 10.1016/j.neuint.2022.105313] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/20/2022] [Accepted: 02/20/2022] [Indexed: 10/19/2022]
Abstract
Transthyretin (TTR), which is one of the major amyloidogenic proteins in systemic amyloidosis, forms extracellular amyloid deposits in the systemic organs such as nerves, ligaments, heart, and arterioles, and causes two kinds of systemic amyloidosis, hereditary ATTR (ATTRv) amyloidosis induced by variant TTR and aging-related wild-type ATTR (ATTRwt) amyloidosis. More than 150 different mutations, most of which are amyloidogenic, have been reported in the TTR gene. Since most disease-associated mutations affect TTR tetramer dissociation rates, destabilization of TTR tetramers is widely believed to be a critical step in TTR amyloid formation. Recently, effective disease-modifying therapies such as TTR tetramer stabilizers and TTR gene silencing therapies have been developed for ATTR amyloidosis. This study reviews the clinical phenotypes of ATTR amyloidosis, TTR features, and recent progress in promising therapies for ATTR amyloidosis.
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Affiliation(s)
- Mitsuharu Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-0811, Japan.
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13
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Proteome alterations in the aqueous humor reflect structural and functional phenotypes in patients with advanced normal-tension glaucoma. Sci Rep 2022; 12:1221. [PMID: 35075201 PMCID: PMC8786875 DOI: 10.1038/s41598-022-05273-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 12/23/2021] [Indexed: 12/28/2022] Open
Abstract
Previous reports have shown possible association between altered protein levels in aqueous humor (AH) and normal-tension glaucoma (NTG), but the underlying pathogenetic mechanism as well as specific molecular biomarkers for NTG remains still elusive. Here, we aimed to identify novel biomarkers for advanced NTG by analyzing the proteome of patient-derived AH and their correlation with various functional and structural parameters from the visual field test (VF), optical coherence tomography (OCT), and OCT angiography (OCTA). We determined differentially expressed proteins (DEPs) of the AH of patients with advanced NTG (n = 20) using label-free quantitative (LFQ) proteomics with pooled samples and data-independent acquisition (DIA) analysis with individual samples, and the roles of AH DEPs in biological pathways were evaluated using bioinformatics. We identified 603 proteins in the AH of patients with advanced NTG, and 61 of them were selected as DEPs via global proteome LFQ profiling. Individual DIA analyses identified a total of 12 DEPs as biomarker candidates, seven of which were upregulated, and five were downregulated. Gene ontology enrichment analysis revealed that those DEPs were mainly involved in the immune response. Moreover, IGFBP2, ENO1, C7, B2M, AMBP, DSP, and DCD showed a significant correlation with the mean deviation of VF and with peripapillary and macular parameters from OCT and OCTA. The present study provides possible molecular biomarkers for the diagnosis of advanced NTG.
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14
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Auler N, Tonner H, Pfeiffer N, Grus FH. Antibody and Protein Profiles in Glaucoma: Screening of Biomarkers and Identification of Signaling Pathways. BIOLOGY 2021; 10:biology10121296. [PMID: 34943212 PMCID: PMC8698915 DOI: 10.3390/biology10121296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/24/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Glaucoma is a chronic eye disease that is one of the leading causes of blindness worldwide. Currently, the only therapeutic option is to lower intraocular pressure. The onset of the disease is often delayed because patients do not notice visual impairment until very late, which is why glaucoma is also known as “the silent thief of sight”. Therefore, early detection and definition of specific markers, the so-called biomarkers, are immensely important. For the methodical implementation, high-throughput methods and omic-based methods came more and more into focus. Thus, interesting targets for possible biomarkers were already suggested by clinical research and basic research, respectively. This review article aims to join the findings of the two disciplines by collecting overlaps as well as differences in various clinical studies and to shed light on promising candidates concerning findings from basic research, facilitating conclusions on possible therapy options. Abstract Glaucoma represents a group of chronic neurodegenerative diseases, constituting the second leading cause of blindness worldwide. To date, chronically elevated intraocular pressure has been identified as the main risk factor and the only treatable symptom. However, there is increasing evidence in the recent literature that IOP-independent molecular mechanisms also play an important role in the progression of the disease. In recent years, it has become increasingly clear that glaucoma has an autoimmune component. The main focus nowadays is elucidating glaucoma pathogenesis, finding early diagnostic options and new therapeutic approaches. This review article summarizes the impact of different antibodies and proteins associated with glaucoma that can be detected for example by microarray and mass spectrometric analyzes, which (i) provide information about expression profiles and associated molecular signaling pathways, (ii) can possibly be used as a diagnostic tool in future and, (iii) can identify possible targets for therapeutic approaches.
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15
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Cui QN, Green D, Jethi M, Driver T, Porco TC, Kuo J, Lin SC, Stamper RL, Han Y, Chiu CS, Ramanathan S, Ward ME, Possin K, Ou Y. Individuals with and without normal tension glaucoma exhibit comparable performance on tests of cognitive function. Int J Ophthalmol 2021; 14:1721-1728. [PMID: 34804862 PMCID: PMC8569564 DOI: 10.18240/ijo.2021.11.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 03/16/2021] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate aspects of cognition impacted by individuals with and without normal tension glaucoma. METHODS Fifty normal tension glaucoma (NTG) and 50 control patients ≥50y of age were recruited from the UCSF Department of Ophthalmology. Demographic data and glaucoma parameters were extracted from electronic medical records for both groups. Tests of executive function [Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER)] and learning and memory [California Verbal Learning Test-Second Edition (CVLT-II)] were administered to both NTG and controls. Race, handedness, best-corrected visual acuity, maximum intraocular pressure, optic nerve cup-to-disc ratio, visual field and optic nerve optical coherence tomography parameters, and a measure of general health (Charlson Comorbidity Index) were compared between NTG and controls as well as within NTG subgroups. Multivariate linear regression was used to compare group performances on the EXAMINER battery and CVLT-II while controlling for age, sex, and years of education. RESULTS NTG and controls were comparable with respect to age, sex, race, education, handedness, and the Charlson Comorbidity Index (P>0.05 for all). Performance on the EXAMINER composite score and the CVLT-II did not differ between NTG and controls (P>0.05 for both). CONCLUSION This is the first prospective study in which the cognitive function of subject with NTG were evaluated using a comprehensive, computerized neurocognitive battery. Subjects with NTG do not perform worse than unaffected controls on tests of executive function, learning, and memory. Results do not support the hypothesis that individuals with NTG are at higher risk for cognitive dysfunction and/or dementia.
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Affiliation(s)
- Qi N. Cui
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
- University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - David Green
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Mohit Jethi
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Todd Driver
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Travis C. Porco
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
- Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California 94143, USA
| | - Jane Kuo
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Shan C. Lin
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
- Glaucoma Center of San Francisco, San Francisco, California 94105, USA
| | - Robert L. Stamper
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Ying Han
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Cynthia S. Chiu
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Saras Ramanathan
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
| | - Michael E. Ward
- Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Katherine Possin
- Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA
| | - Yvonne Ou
- Department of Ophthalmology, University of California San Francisco, San Francisco, California 94143, USA
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16
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Hayashi H, Mori M, Harashima M, Hashizume T, Furiya M, Mukaigaito C, Takemura E, Yamada M, Mise K, Yuan B, Takagi N. Apolipoprotein E-Containing Lipoproteins and LRP1 Protect From NMDA-Induced Excitotoxicity Associated With Reducing α2-Macroglobulin in Müller Glia. Invest Ophthalmol Vis Sci 2021; 62:23. [PMID: 34698771 PMCID: PMC8556555 DOI: 10.1167/iovs.62.13.23] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Purpose Optic nerve damage leads to impairment of visual functions. We previously demonstrated that apolipoprotein E-containing lipoproteins (E-LPs) protect retinal ganglion cells (RGCs) from degeneration in a glaucoma model of glutamate/aspartate transporter-deficient mice. This study aimed to determine whether E-LPs protect RGCs from N-methyl-d-aspartate (NMDA)-induced excitotoxicity, and to investigate the details of an indirect neuroprotective mechanism of E-LPs by reducing α2-macroglobulin, which interferes with the neuroprotective effect of E-LPs, in Müller glia. Methods Excitotoxicity was caused by intravitreal injection of NMDA, and then retinae were subjected to immunoblotting or quantitative reverse transcription-PCR. Primary cultures of mouse mixed retinal cells and mouse Müller glia were used for evaluating the effects of E-LPs on the expression of α2-macroglobulin. Results Intravitreal injection of E-LPs protected the optic nerve from degeneration and attenuated the increase in α2-macroglobulin in aqueous humor and retina of rats. E-LPs directly decreased the expression and secretion of α2-macroglobulin in primary cultures of Müller glia; this decrease in production of α2-macroglobulin was blocked by knockdown of the low-density lipoprotein receptor-related protein 1 (LRP1) with small interfering RNA. E-LPs promoted the phosphorylation of STAT3, whereas Stattic, an inhibitor of STAT3, restored the expression of α2-macroglobulin decreased by E-LPs. Conclusions In addition to our previous findings of the protection of RGCs by E-LPs, the new observations in Müller glia indicate that a reduction of the intraocular α2-macroglobulin, regulated by the E-LP-LRP1-STAT3 pathway, might be an additional protective mechanism against excitotoxicity in the retina.
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Affiliation(s)
- Hideki Hayashi
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Misuzu Mori
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Mina Harashima
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Tatsuya Hashizume
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Miho Furiya
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Chihaya Mukaigaito
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Emi Takemura
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Mariko Yamada
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Kanako Mise
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Bo Yuan
- Laboratory of Pharmacology, School of Pharmacy, Josai University, Sakado, Saitama, Japan
| | - Norio Takagi
- Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
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17
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Patel PA, Lee TJ, Kodeboyina SK, Jones G, Bollinger K, Ulrich L, Bogorad D, Estes A, Zhi W, Sharma S, Sharma A. Intra-population differences of apolipoproteins in the aqueous humor. Lipids Health Dis 2021; 20:128. [PMID: 34602085 PMCID: PMC8487476 DOI: 10.1186/s12944-021-01555-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Evidence suggests that proteins related to lipid metabolism, such as apolipoproteins, play an important role in the maintenance of normal vision. While several members of the apolipoprotein family are abundant in human aqueous humor (AH), their study remains difficult due to the AH's small volume, low protein concentration, and the invasive nature of sample collection. In this study, we report the use of Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to discover associations between AH apolipoproteins and race, gender, and ocular structure in patients with and without primary open angle glaucoma (POAG). METHODS AH samples were collected from 231 patients undergoing phacoemulsification or glaucoma incisional surgery at the Medical College of Georgia, Augusta University and subsequently analyzed via LC-MS/MS. The number of peptide spectrum matches (PSMs) for each protein was used as a semi-quantitative measure of relative protein levels. Parameters related to ocular structure were determined using Optical Coherence Tomography (OCT) and Heidelberg Retinal Tomography (HRT). These data sets were probed for relationships between apolipoprotein levels and POAG, demographics (gender and race), and ocular structure. RESULTS A total of ten apolipoproteins were detected in the 231 collected AH samples, with six detected in 100% of the samples, one detected in almost 57% of the samples and three detected in less than 10% of the samples. The levels of APOA1, APOC3, and APOD were higher among POAG subjects. Stratification by gender and race revealed demographic-specific variations. The levels of five apolipoproteins (APOA1, APOA2, APOA4, APOC3, and APOD) were higher in female POAG patients, whereas no apolipoprotein levels were altered in male POAG patients. The levels of APOA1, APOA2, APOA4, and APOD were increased in glaucomatous African American patients, whereas APOE and APOH levels were decreased in glaucomatous Caucasian patients. We also found distinct associations between apolipoprotein levels and OCT and HRT parameters in patients with and without POAG. CONCLUSIONS The intra-population variation in apolipoprotein levels highlights the heterogeneity of glaucoma as a disease, suggesting the importance of personalized treatments. Gender and race-specific alterations may be associated with higher risks of POAG in females and members of the African American population.
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Affiliation(s)
- Parth A Patel
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
| | - Tae Jin Lee
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
| | - Sai Karthik Kodeboyina
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
- Mass General Brigham, 215 First Street, Cambridge, MA, 02142, USA
| | - Garrett Jones
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
| | - Kathryn Bollinger
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Lane Ulrich
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - David Bogorad
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Amy Estes
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Wenbo Zhi
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
| | - Shruti Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA4094, Augusta, GA, 30912, USA.
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
- Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
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18
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Tezel G. Multiplex protein analysis for the study of glaucoma. Expert Rev Proteomics 2021; 18:911-924. [PMID: 34672220 PMCID: PMC8712406 DOI: 10.1080/14789450.2021.1996232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/15/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Glaucoma, a leading cause of irreversible blindness in the world, is a chronic neurodegenerative disease of multifactorial origin. Extensive research is ongoing to better understand, prevent, and treat progressive degeneration of retinal ganglion cells in glaucoma. While experimental models of glaucoma and postmortem tissues of human donors are analyzed for pathophysiological comprehension and improved treatment of this blinding disease, clinical samples of intraocular biofluids and blood collected from glaucoma patients are analyzed to identify predictive, diagnostic, and prognostic biomarkers. Multiplexing techniques for protein analysis offer a valuable approach for translational glaucoma research. AREAS COVERED This review provides an overview of the increasing applications of multiplex protein analysis for glaucoma research and also highlights current research challenges in the field and expected solutions from emerging technological advances. EXPERT OPINION Analytical techniques for multiplex analysis of proteins can help uncover neurodegenerative processes for enhanced treatment of glaucoma and can help identify molecular biomarkers for improved clinical testing and monitoring of this complex disease. This evolving field and continuously growing availability of new technologies are expected to broaden the comprehension of this complex neurodegenerative disease and speed up the progress toward new therapeutics and personalized patient care to prevent blindness from glaucoma.
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Affiliation(s)
- Gülgün Tezel
- Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University, Edward S. Harkness Eye Institute, New York, NY, USA
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19
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Cueto AFV, Álvarez L, García M, Álvarez-Barrios A, Artime E, Cueto LFV, Coca-Prados M, González-Iglesias H. Candidate Glaucoma Biomarkers: From Proteins to Metabolites, and the Pitfalls to Clinical Applications. BIOLOGY 2021; 10:763. [PMID: 34439995 PMCID: PMC8389649 DOI: 10.3390/biology10080763] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 12/17/2022]
Abstract
Glaucoma is an insidious group of eye diseases causing degeneration of the optic nerve, progressive loss of vision, and irreversible blindness. The number of people affected by glaucoma is estimated at 80 million in 2021, with 3.5% prevalence in people aged 40-80. The main biomarker and risk factor for the onset and progression of glaucoma is the elevation of intraocular pressure. However, when glaucoma is diagnosed, the level of retinal ganglion cell death usually amounts to 30-40%; hence, the urgent need for its early diagnosis. Molecular biomarkers of glaucoma, from proteins to metabolites, may be helpful as indicators of pathogenic processes observed during the disease's onset. The discovery of human glaucoma biomarkers is hampered by major limitations, including whether medications are influencing the expression of molecules in bodily fluids, or whether tests to validate glaucoma biomarker candidates should include human subjects with different types and stages of the disease, as well as patients with other ocular and neurodegenerative diseases. Moreover, the proper selection of the biofluid or tissue, as well as the analytical platform, should be mandatory. In this review, we have summarized current knowledge concerning proteomics- and metabolomics-based glaucoma biomarkers, with specificity to human eye tissue and fluid, as well the analytical approach and the main results obtained. The complex data published to date, which include at least 458 different molecules altered in human glaucoma, merit a new, integrative approach allowing for future diagnostic tests based on the absolute quantification of local and/or systemic biomarkers of glaucoma.
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Affiliation(s)
- Andrés Fernández-Vega Cueto
- Instituto Oftalmológico Fernández-Vega, Avda. Dres. Fernández-Vega, 34, 33012 Oviedo, Spain; (A.F.-V.C.); (M.G.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Lydia Álvarez
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Montserrat García
- Instituto Oftalmológico Fernández-Vega, Avda. Dres. Fernández-Vega, 34, 33012 Oviedo, Spain; (A.F.-V.C.); (M.G.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Ana Álvarez-Barrios
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Enol Artime
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Luis Fernández-Vega Cueto
- Instituto Oftalmológico Fernández-Vega, Avda. Dres. Fernández-Vega, 34, 33012 Oviedo, Spain; (A.F.-V.C.); (M.G.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
| | - Miguel Coca-Prados
- Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06510, USA;
| | - Héctor González-Iglesias
- Instituto Oftalmológico Fernández-Vega, Avda. Dres. Fernández-Vega, 34, 33012 Oviedo, Spain; (A.F.-V.C.); (M.G.)
- Instituto Universitario Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain; (L.Á.); (A.Á.-B.); (E.A.)
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20
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Fan J, Qiu L, Qiao Y, Xue M, Dong X, Meng Z. Recent Advances in Sensing Applications of Molecularly Imprinted Photonic Crystals. Front Chem 2021; 9:665119. [PMID: 34195173 PMCID: PMC8236589 DOI: 10.3389/fchem.2021.665119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/26/2021] [Indexed: 11/30/2022] Open
Abstract
Photonic crystals (PhCs) with a brightly colored structure are novel materials and are widely used in chemical and biological sensing. Combining PhCs with molecular imprinting technology (MIT), the molecularly imprinted PhC (MIPC) sensors are fabricated, which can specifically recognize the target molecules. Aside from high sensitivity and selectivity, the MIPC sensors could recognize the naked eye detection because of its optical properties. In this review, an overview of recent advances in sensing applications of MIPC sensors including the responsive mechanisms, application in environmental monitoring, and the application to human health were illustrated. The MIPC sensors all responded to the analytes specifically and also showed high sensitivity in real samples, which provided a method to realize the rapid, convenient, naked eye, and real-time detection. Furthermore, the current limitations and potential future directions of MIPC sensors were also discussed.
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Affiliation(s)
- Jing Fan
- School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
| | - Lili Qiu
- School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
| | - Yu Qiao
- School of Design and Arts, Beijing Institute of Technology, Beijing, China
| | - Min Xue
- School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
| | - Xiao Dong
- School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
| | - Zihui Meng
- School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China
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21
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Chalkias IN, Tegos T, Topouzis F, Tsolaki M. Ocular biomarkers and their role in the early diagnosis of neurocognitive disorders. Eur J Ophthalmol 2021; 31:2808-2817. [PMID: 34000876 DOI: 10.1177/11206721211016311] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Given the fact that different types of dementia can be diagnosed only postmortem or when the disease has progressed enough to cause irreversible damage to certain brain areas, there has been an increasing need for the development of sensitive and reliable methods that can detect early preclinical forms of dementia, before the symptoms have even appeared. Ideally, such a method would have the following characteristics: to be inexpensive, sensitive and specific, Non-invasive, fast and easily accessible. The ophthalmologic examination and especially the study of the retina, has caught the attention of many researchers, as it can provide a lot of information about the CNS and it fulfills many of the aforementioned criteria. Since the introduction of the non-invasive optical coherence tomography (OCT) and the newly developed modality OCT-angiography (OCT-A) that can demonstrate the structure and the microvasculature of the retina and choroid, respectively, there have been promising results regarding the value of the ophthalmologic examination in the early diagnosis of Alzheimer's disease. In this review paper, we summarize and discuss the ocular findings in patients with cognitive impairment disorders and we highlight the importance of the ophthalmologic examination to the diagnosis of these disorders.
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Affiliation(s)
- Ioannis-Nikolaos Chalkias
- 1st Department of Ophthalmology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece
| | - Thomas Tegos
- 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece
| | - Fotis Topouzis
- 1st Department of Ophthalmology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece
| | - Magda Tsolaki
- 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia Thraki, Greece.,Greek Association of Alzheimer's Disease and Related Disorders, Thessaloniki, Greece
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22
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Kosior-Jarecka E, Czop M, Gasińska K, Wróbel-Dudzińska D, Zalewski DP, Bogucka-Kocka A, Kocki J, Żarnowski T. MicroRNAs in the aqueous humor of patients with different types of glaucoma. Graefes Arch Clin Exp Ophthalmol 2021; 259:2337-2349. [PMID: 33929592 PMCID: PMC8352835 DOI: 10.1007/s00417-021-05214-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 01/01/2023] Open
Abstract
Purpose The aim of the study was to compare the frequency and the level of expression of selected miRNAs in the aqueous humor of patients with various types of glaucoma. Methods The studied group consisted of 42 patients with glaucoma: 19 with primary open-angle glaucoma (POAG), 14 with pseudoexfoliation glaucoma (PEXG), 9 with primary angle closure glaucoma (PACG), and the control group of 36 patients with senile cataract without glaucoma. The real-time polymerase chain reaction method was used to analyze the expression of miRNAs. Results There were no significant differences in the frequency and the level of miRNA expression between various types of glaucoma. There was a tendency for hsa-miR-6722-3p and hsa-miR-184 to be expressed more frequently in PEXG and hsa-miR-1260b in POAG. The expression levels of hsa-miR-1260b and hsa-miR-6515-3p were correlated with age in POAG. Target annotation and functional analyses showed that genes targeted by the most frequently expressed miRNAs (hsa-miR-1202, -1260b, -184, -187-5p, -6515-3p, -6722-3p, and hsa-mir-4634) are involved mainly in response to hypoxia, cardiovascular system development, and apoptosis. Conclusion Hsa-miR-1260b was the most abundantly expressed among studied miRNAs and may be a potential biomarker of clinical status in PEXG and PACG. Supplementary Information The online version contains supplementary material available at 10.1007/s00417-021-05214-z.
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Affiliation(s)
- Ewa Kosior-Jarecka
- Department of Diagnostics and Microsurgery of Glaucoma, Medical University of Lublin, ul. Chmielna 1, 20-079, Lublin, Poland
| | - Marcin Czop
- Department of Clinical Genetics, Medical University of Lublin, ul. Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Karolina Gasińska
- Department of Diagnostics and Microsurgery of Glaucoma, Medical University of Lublin, ul. Chmielna 1, 20-079, Lublin, Poland.
| | - Dominika Wróbel-Dudzińska
- Department of Diagnostics and Microsurgery of Glaucoma, Medical University of Lublin, ul. Chmielna 1, 20-079, Lublin, Poland
| | - Daniel P Zalewski
- Department of Biology and Genetics, Medical University of Lublin, ul. Chodźki 4a, 20-093, Lublin, Poland
| | - Anna Bogucka-Kocka
- Department of Biology and Genetics, Medical University of Lublin, ul. Chodźki 4a, 20-093, Lublin, Poland
| | - Janusz Kocki
- Department of Clinical Genetics, Medical University of Lublin, ul. Radziwiłłowska 11, 20-080, Lublin, Poland
| | - Tomasz Żarnowski
- Department of Diagnostics and Microsurgery of Glaucoma, Medical University of Lublin, ul. Chmielna 1, 20-079, Lublin, Poland
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23
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Hanekamp S, Ćurčić-Blake B, Caron B, McPherson B, Timmer A, Prins D, Boucard CC, Yoshida M, Ida M, Hunt D, Jansonius NM, Pestilli F, Cornelissen FW. White matter alterations in glaucoma and monocular blindness differ outside the visual system. Sci Rep 2021; 11:6866. [PMID: 33767217 PMCID: PMC7994383 DOI: 10.1038/s41598-021-85602-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 02/15/2021] [Indexed: 01/23/2023] Open
Abstract
The degree to which glaucoma has effects in the brain beyond the eye and the visual pathways is unclear. To clarify this, we investigated white matter microstructure (WMM) in 37 tracts of patients with glaucoma, monocular blindness, and controls. We used brainlife.io for reproducibility. White matter tracts were subdivided into seven categories ranging from those primarily involved in vision (the visual white matter) to those primarily involved in cognition and motor control. In the vision tracts, WMM was decreased as measured by fractional anisotropy in both glaucoma and monocular blind subjects compared to controls, suggesting neurodegeneration due to reduced sensory inputs. A test-retest approach was used to validate these results. The pattern of results was different in monocular blind subjects, where WMM properties increased outside the visual white matter as compared to controls. This pattern of results suggests that whereas in the monocular blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the reorganization as seen in other patient groups following visual loss.
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Affiliation(s)
- Sandra Hanekamp
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
- Department of Intelligent Systems Engineering, Luddy School of Informatics and Engineering, Indiana University, Bloomington, IN, USA.
- Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
| | - Branislava Ćurčić-Blake
- Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bradley Caron
- Program in Neuroscience, Indiana University, Bloomington, IN, USA
- Program in Vision Science, School of Optometry, Indiana University, Bloomington, IN, USA
| | - Brent McPherson
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Anneleen Timmer
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Doety Prins
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Christine C Boucard
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
| | - Masaki Yoshida
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
| | - Masahiro Ida
- Department of Radiology, National Hospital Organization Mito Medical Center, Ibaraki, Japan
| | - David Hunt
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA
| | - Nomdo M Jansonius
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Franco Pestilli
- Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA.
- Department of Intelligent Systems Engineering, Luddy School of Informatics and Engineering, Indiana University, Bloomington, IN, USA.
- Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
- Program in Neuroscience, Indiana University, Bloomington, IN, USA.
- Program in Vision Science, School of Optometry, Indiana University, Bloomington, IN, USA.
| | - Frans W Cornelissen
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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24
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Liu YC, Yam GHF, Lin MTY, Teo E, Koh SK, Deng L, Zhou L, Tong L, Mehta JS. Comparison of tear proteomic and neuromediator profiles changes between small incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK). J Adv Res 2021; 29:67-81. [PMID: 33842006 PMCID: PMC8020296 DOI: 10.1016/j.jare.2020.11.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/29/2020] [Accepted: 11/01/2020] [Indexed: 12/19/2022] Open
Abstract
Introduction The tear proteomics and neuromediators are associated with clinical dry eye parameters following refractive surgery. Purpose To investigate and compare the tear proteomic and neuromediator profiles following small incision lenticule extraction (SMILE) versus laser-assisted in-situ keratomileusis (LASIK). Methods In this randomized controlled trial with paired-eye design, 70 patients were randomized to receive SMILE in one eye and LASIK in the other eye. Tear samples were collected preoperatively, and 1 week, 1, 3, 6 and 12 months postoperatively, and were examined for protein concentration changes using sequential window acquisition of all theoretical fragment ion mass spectrometry (SWATH-MS). The data were analyzed with DAVID Bioinformatics Resources for enriched gene ontology terms and over-represented pathways. Tear neuromediators levels were correlated with clinical parameters. Results Post-SMILE eyes had significantly better Oxford staining scores and tear break-up time (TBUT) than post-LASIK eyes at 1 and 3 months, respectively. Tear substance P and nerve growth factor levels were significantly higher in the LASIK group for 3 months and 1 year, respectively. SMILE and LASIK shared some similar biological responses postoperatively, but there was significant up-regulation in leukocyte migration and wound healing at 1 week, humoral immune response and apoptosis at 1 month, negative regulation of endopeptidase activity at 3 to 6 months, and extracellular structure organization at 1 year in the post-LASIK eyes. Tear mucin-like protein 1 and substance P levels were significantly correlated with TBUT (r = -0.47, r = -0.49, respectively). Conclusion Significant differences in the tear neuromediators and proteomics were observed between SMILE and LASIK, even though clinical dry eye signs have subsided and became comparable between 2 procedures.
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Affiliation(s)
- Yu-Chi Liu
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
- Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Gary Hin-Fai Yam
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
- Department of Ophthalmology, University of Pittsburgh, PA, USA
| | - Molly Tzu-Yu Lin
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
| | - Ericia Teo
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
| | - Siew-Kwan Koh
- Ocular Proteomics, Singapore Eye Research Institute, Singapore
| | - Lu Deng
- Department of Statistics and Applied Probability, Faculty of Science, National University of Singapore, Singapore
| | - Lei Zhou
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
- Ocular Proteomics, Singapore Eye Research Institute, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Louis Tong
- Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Ocular Surface Group, Singapore Eye Research Institute, Singapore
| | - Jodhbir S. Mehta
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
- Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
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25
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Belamkar AV, Mansukhani SA, Savica R, Spiegel MR, Hodge DO, Sit AJ. Incidence of Dementia in Patients With Open-angle Glaucoma: A Population-based Study. J Glaucoma 2021; 30:227-234. [PMID: 33394844 PMCID: PMC8132918 DOI: 10.1097/ijg.0000000000001774] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/11/2020] [Indexed: 11/25/2022]
Abstract
PRECIS In this population-based study of 509 open-angle glaucoma (OAG) patients over a 36-year period, we identified a decreased rate of developing dementia compared with the rate in the general population. PURPOSE The aim was to determine the incidence of dementia and Alzheimer disease (AD) among patients with OAG. PATIENTS AND METHODS Retrospective, population-based cohort study. All residents of Olmsted County, Minnesota (≥40 y) who were diagnosed with OAG between January 1, 1965 and December 31, 2000, were eligible for inclusion in this study. A total of 509 patients were included over the 36-year period. The cumulative probability of developing dementia was calculated and compared with the population risk of dementia. RESULTS Of the 509 patients included, 300 (58.9%) were female, the median age was 67.5 years, and 278 patients (54.6%) had primary OAG. Other subgroups were pseudoexfoliation in 15.1%, treated ocular hypertension in 14.1%, normal tension glaucoma in 10.6%, and pigmentary glaucoma in 5.5% of the patients. Respectively, 118 (23.0%) and 99 (19.4%) patients developed dementia and AD. The 10-year cumulative probability of developing dementia and AD was 12.0% and 9.9%, with a 95% confidence interval of 9.3%-15.3% and 7.5%-13%, respectively. The observed 10-year incidence of dementia and AD were significantly lower than the expected population incidence (19.0% and 19.0%; P<0.001). Older age at diagnosis of glaucoma was a strong predictor for the development of dementia by multivariate analysis (hazard ratio: 3.31, 95% confidence interval: 2.61-4.20, P<0.001). CONCLUSION The risk of developing dementia or AD was decreased in OAG patients compared with the general population. OAG with onset at a later age may present as a different etiopathogenetic entity compared with onset at a younger age, and represent the optic nerve findings of generalized neurodegenerative processes.
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Affiliation(s)
| | | | - Rodolfo Savica
- Department of Neurology, Mayo Clinic, Rochester,
Minnesota
| | - Matthew R. Spiegel
- Department of Health Sciences Research, Mayo Clinic,
Jacksonville, Florida
| | - David O. Hodge
- Department of Health Sciences Research, Mayo Clinic,
Jacksonville, Florida
| | - Arthur J. Sit
- Department of Ophthalmology, Mayo Clinic, Rochester,
Minnesota
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26
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Yu P, Dong WP, Tang YB, Chen HZ, Cui YY, Bian XL. Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:332. [PMID: 33708959 PMCID: PMC7944337 DOI: 10.21037/atm-20-8093] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/29/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. METHODS The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD). RESULTS HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGD-induced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA. CONCLUSIONS HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical application of HupA and other AChEIs for glaucoma patients should be further investigated.
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Affiliation(s)
- Ping Yu
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Pei Dong
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of General Surgery, Hernia and Abdominal Wall Surgery Center of Shanghai Jiao Tong University, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya-Bin Tang
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hong-Zhuan Chen
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Yao Cui
- Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Lan Bian
- Department of Pharmacy, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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27
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Margeta MA, Letcher SM, Igo RP, Cooke Bailey JN, Pasquale LR, Haines JL, Butovsky O, Wiggs JL. Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4. Invest Ophthalmol Vis Sci 2021; 61:3. [PMID: 32614373 PMCID: PMC7425753 DOI: 10.1167/iovs.61.8.3] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Purpose Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature. Methods APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex. Results In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74–0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70–0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58–0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05). Conclusions We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.
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28
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Kodeboyina SK, Lee TJ, Churchwell L, Ulrich L, Bollinger K, Bogorad D, Estes A, Zhi W, Sharma S, Sharma A. The Constitutive Proteome of Human Aqueous Humor and Race Specific Alterations. Proteomes 2020; 8:proteomes8040034. [PMID: 33217969 PMCID: PMC7709111 DOI: 10.3390/proteomes8040034] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 12/29/2022] Open
Abstract
Aqueous humor (AH) is the fluid in the anterior and posterior chambers of the eye that contains proteins regulating ocular homeostasis. Analysis of aqueous humor proteome is challenging, mainly due to low sample volume and protein concentration. In this study, by utilizing state of the art technology, we performed Liquid-Chromatography Mass spectrometry (LC-MS/MS) analysis of 88 aqueous humor samples from subjects undergoing cataract surgery. A total of 2263 unique proteins were identified, which were sub-divided into four categories that were based on their detection in the number of samples: High (n = 152), Medium (n = 91), Low (n = 128), and Rare (n = 1892). A total of 243 proteins detected in at least 50% of the samples were considered as the constitutive proteome of human aqueous humor. The biological processes and pathways enriched in the AH proteins mainly include vesicle mediated transport, acute phase response signaling, LXR/RXR activation, complement system, and secretion. The enriched molecular functions are endopeptidase activity, and various binding functions, such as protein binding, lipid binding, and ion binding. Additionally, this study provides a novel insight into race specific differences in the AH proteome. A total of six proteins were upregulated, and five proteins were downregulated in African American subjects as compared to Caucasians.
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Affiliation(s)
- Sai Karthik Kodeboyina
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
| | - Tae Jin Lee
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
| | - Lara Churchwell
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
| | - Lane Ulrich
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
| | - Kathryn Bollinger
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
| | - David Bogorad
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
| | - Amy Estes
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
| | - Wenbo Zhi
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
| | - Shruti Sharma
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 30912, USA; (S.K.K.); (T.J.L.); (L.C.); (W.Z.); (S.S.)
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA; (L.U.); (K.B.); (D.B.); (A.E.)
- Department of Population Health Sciences, Augusta University, Augusta, GA 30912, USA
- Correspondence:
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Cappelli F, Caudano F, Marenco M, Testa V, Masala A, Sindaco D, Macrì A, Traverso CE, Iester M, Ricciarelli R. Evaluating the Correlation between Alzheimer's Amyloid-β Peptides and Glaucoma in Human Aqueous Humor. Transl Vis Sci Technol 2020; 9:21. [PMID: 32821493 PMCID: PMC7401938 DOI: 10.1167/tvst.9.5.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 02/23/2020] [Indexed: 11/19/2022] Open
Abstract
Purpose Recent studies suggest that glaucoma may share common pathogenic mechanisms with Alzheimer's disease. To test this hypothesis, we investigated the correlation between glaucoma and amyloid-β42 (Aβ42) concentration in human samples of aqueous humor (AH). Methods Eighty-one candidates for cataract or glaucoma surgery were consecutively enrolled, with a median age of 77 years; of these, 32 subjects were affected by glaucoma and 49 were controls. Before surgery, each patient received an ophthalmological examination including biometry, intraocular pressure (IOP) measurement, fundus photography, and determination of the mean thickness of the ganglion cell complex (GCC) and/or retinal nerve fiber layer. During the surgical procedure, an AH sample was collected and immediately processed for total protein (TP) and Aβ42 evaluation. Results Aβ42 levels were not statistically different between the glaucomatous and control samples, but a significant increase in TP concentration was found in the AH of glaucoma patients compared with controls (P = 0.02). In addition, positive correlations were observed between TP and Aβ42 (r = 0.51; P < 0.0001), between TP and IOP (r = 0.44; P < 0.0001), and between Aβ42 and IOP (r = 0.22; P = 0.033). Conclusions Our results indicate that an increased protein concentration in the AH could play a role in the pathogenesis of glaucomatous disease. Translational Relevance This study strongly supports the hypothesis that increased TP in the AH may have a pathogenic role in glaucoma. Further investigations are needed to clarify whether the protein enhancement represents a causative factor and whether it can be used as a marker of disease or as a novel therapeutic target.
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Affiliation(s)
- Francesca Cappelli
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Francesca Caudano
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Maria Marenco
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Valeria Testa
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | | | - Daniele Sindaco
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy
| | - Angelo Macrì
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Carlo E Traverso
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Michele Iester
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Roberta Ricciarelli
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Shin MK, Ji YW, Moon CE, Lee H, Kang B, Jinn WS, Ki J, Mun B, Kim MH, Lee HK, Haam S. Matrix metalloproteinase 9-activatable peptide-conjugated hydrogel-based fluorogenic intraocular-lens sensor. Biosens Bioelectron 2020; 162:112254. [DOI: 10.1016/j.bios.2020.112254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 04/04/2020] [Accepted: 04/26/2020] [Indexed: 12/16/2022]
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Interplay between Oxidative Stress, Inflammation, and Amyloidosis in the Anterior Segment of the Eye; Its Pathological Implications. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6286105. [PMID: 32566091 PMCID: PMC7291327 DOI: 10.1155/2020/6286105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/02/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022]
Abstract
There are different pathologies associated with amyloidogenic processes caused by the increase of reactive oxygen species (ROS) and the overactivation of inflammatory responses. These alterations are present in different regions of the anterior segment of the eye, and they have been associated with the development and progression of ocular pathologies, such as glaucoma, dry eye syndrome, keratitis, and cataracts among other pathologies. Aim. To discuss briefly the anatomical characteristics of the anterior segment of the eye and describe the interaction between oxidative stress (OS) and inflammatory responses, emphasizing the misfolding of several proteins leading to amyloidogenic processes occurring in the anterior segment and their implications in the development of ocular diseases. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms “eye,” “anterior segment”, “inflammation”, “oxidative stress”, and “amyloidosis”. The search encompassed manuscripts published up to April 2019. A hundred forty-four published studies met the inclusion criteria. We present the current knowledge regarding the interaction between OS and the activation of inflammatory processes and how both can cause conformational changes in several peptides and proteins in each compartment of the anterior segment. However, we found that there is no consensus about which factor is the first to cause amyloidosis. Our conclusions suggest that there is an interplay among these factors forming a vicious cycle that leads to the loss of protein structure in ocular pathologies, and multifactorial therapies should be developed to avoid protein misfolding and to stop the progression of ocular pathologies.
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Abstract
Exfoliation syndrome (XFS) is a common age-related matrix process resulting from excessive production and disordered assembly of elastic microfibrillar components into highly cross-linked fibrillary aggregates throughout the anterior eye segment and various organ systems. The underlying molecular pathophysiology involves a complex interplay of profibrotic protagonists including growth factors, proteolytic enzymes and inhibitors, proinflammatory cytokines, chaperones, and dysregulated stress response pathways including insufficient autophagy. Interaction between individual genetic predisposition and stress factors is a plausible theory explaining the development of XFS in the aging individual. Genome-wide association studies have identified robust genetic associations with LOXL1, CACNA1A, and 5 additional genes including POMP and TMEM136, which provide new biological insights into the pathology of XFS and highlight a role for abnormal matrix cross-linking processes, Ca channel deficiency, blood-aqueous barrier dysfunction, and abnormal ubiquitin-proteasome signaling in XFS pathophysiology. However, the exact pathophysiological mechanisms, the functional role of genetic risk variants, and gene-environment interactions still remain to be characterized.
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Nikhalashree S, George R, Shantha B, Lingam V, Vidya W, Panday M, Sulochana KN, Coral K. Detection of Proteins Associated with Extracellular Matrix Regulation in the Aqueous Humour of Patients with Primary Glaucoma. Curr Eye Res 2019; 44:1018-1025. [DOI: 10.1080/02713683.2019.1608261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Sampath Nikhalashree
- R.S. Mehta Jain Department of Biochemistry and Cell Biology, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai, India
- School of Chemical and Biotechnology, SASTRA Deemed-to-be University, Thanjavur, India
| | - Ronnie George
- Smt Jadhavbai Nathmal Singhvee Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Balekudaru Shantha
- Smt Jadhavbai Nathmal Singhvee Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Vijaya Lingam
- Smt Jadhavbai Nathmal Singhvee Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Wadke Vidya
- Smt Jadhavbai Nathmal Singhvee Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | - Manish Panday
- Smt Jadhavbai Nathmal Singhvee Glaucoma Services, Medical Research Foundation, Sankara Nethralaya, Chennai, India
| | | | - Karunakaran Coral
- R.S. Mehta Jain Department of Biochemistry and Cell Biology, KBIRVO, Vision Research Foundation, Sankara Nethralaya, Chennai, India
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34
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Dehghani C, Frost S, Jayasena R, Masters CL, Kanagasingam Y. Ocular Biomarkers of Alzheimer's Disease: The Role of Anterior Eye and Potential Future Directions. Invest Ophthalmol Vis Sci 2019; 59:3554-3563. [PMID: 30025102 DOI: 10.1167/iovs.18-24694] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Globally, Alzheimer's disease (AD) is a growing health and economic challenge that has no effective cure. Recent clinical trials indicate that preclinical treatment may be required but a routine screening tool for AD has been elusive. Hence, a simple, yet sensitive biomarker for preclinical AD, when the disease is most likely to be amenable to treatment, is lacking. Due to several features, the eye has been explored for this purpose and, among the ocular tissues, the retina has received the most attention. Currently, major works investigating the potential AD diagnosis by detecting amyloid-β (Aβ) signatures in the retinal tissue are underway, while the anterior eye is more accessible for in vivo imaging and examination. This report provides a concise review of current literature on the anterior eye components, including the crystalline lens, cornea, and aqueous humor, in AD. We also discuss the potential for assessment of the corneal nerve structure and regeneration as well as conjunctival tissue for AD-related alterations. The crystalline lens has received considerable attention, but further research is required to confirm whether Aβ accumulates in the lens and whether it mirrors brain neuropathologic changes, particularly in preclinical AD. The rich corneal neural network and conjunctival vasculature also merit exploration in future studies to shed light on their potential association with AD pathologic changes.
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Affiliation(s)
- Cirous Dehghani
- Australian e-Health Research Center, CSIRO, Parkville, Australia
| | - Shaun Frost
- Australian e-Health Research Center, CSIRO, Perth, Australia
| | - Rajiv Jayasena
- Australian e-Health Research Center, CSIRO, Parkville, Australia
| | - Colin L Masters
- The Florey Institute, The University of Melbourne, Parkville, Australia
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Review of Biomarkers in Ocular Matrices: Challenges and Opportunities. Pharm Res 2019; 36:40. [PMID: 30673862 PMCID: PMC6344398 DOI: 10.1007/s11095-019-2569-8] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/07/2019] [Indexed: 02/05/2023]
Abstract
Biomarkers provide a powerful and dynamic approach to improve our understanding of the mechanisms underlying ocular diseases with applications in diagnosis, disease modulation or for predicting and monitoring of clinical response to treatment. Defined as measurable indicator of normal or pathological processes, biomarker evaluation has been used extensively in drug development within clinical settings to better comprehend effectiveness of treatment in ocular diseases. Biomarkers in the eye have the advantage of access to multiple ocular matrices via minimally invasive methods. Repeat sampling for biomarker assessment has enabled reproducible objective measures of disease process or biological responses to a drug treatment. This review describes the usage of biomarkers with respect to four commonly sampled ocular matrices in clinic: tears, conjunctiva, aqueous humor and vitreous. Issues that affect the evaluation of biomarkers are discussed along with opportunities to leverage biomarkers such that ultimately, they can be used for customized targeted therapy.
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36
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Jinn WS, Shin MK, Kang B, Oh S, Moon CE, Mun B, Ji YW, Lee HK, Haam S. A visually distinguishable light interfering bioresponsive silica nanoparticle hydrogel sensor fabricated through the molecular imprinting technique. J Mater Chem B 2019; 7:7120-7128. [DOI: 10.1039/c9tb01579e] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Methods of the early detection of diseases are based on recognition of the smallest change in the levels of a disease-specific biomarker in body fluids.
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Affiliation(s)
- Woo Seok Jinn
- Department of Chemical and Biomolecular Engineering
- College of Engineering
- Yonsei University
- Seoul 120-749
- Republic of Korea
| | - Moo-Kwang Shin
- Department of Chemical and Biomolecular Engineering
- College of Engineering
- Yonsei University
- Seoul 120-749
- Republic of Korea
| | - Byunghoon Kang
- BioNanotechnology Research Center
- Korea Research Institue of Bioscience and Biotechnology(KRIBB)
- Daejeon 34141
- Republic of Korea
| | - Seungjae Oh
- Department of Radiology
- College of Medicine
- Yonsei University
- Seoul 120-752
- Republic of Korea
| | - Chae-Eun Moon
- Department of Ophthalmology
- College of Medicine
- Yonsei University
- Seoul 120-752
- Republic of Korea
| | - Byeonggeol Mun
- Department of Chemical and Biomolecular Engineering
- College of Engineering
- Yonsei University
- Seoul 120-749
- Republic of Korea
| | - Yong Woo Ji
- Department of Ophthalmology
- National Health Insurance Service Ilsan Hospital
- Goyang 10444
- Republic of Korea
| | - Hyung Keun Lee
- Department of Ophthalmology
- College of Medicine
- Yonsei University
- Seoul 120-752
- Republic of Korea
| | - Seungjoo Haam
- Department of Chemical and Biomolecular Engineering
- College of Engineering
- Yonsei University
- Seoul 120-749
- Republic of Korea
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37
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Mancino R, Martucci A, Cesareo M, Giannini C, Corasaniti MT, Bagetta G, Nucci C. Glaucoma and Alzheimer Disease: One Age-Related Neurodegenerative Disease of the Brain. Curr Neuropharmacol 2018; 16:971-977. [PMID: 29210654 PMCID: PMC6120118 DOI: 10.2174/1570159x16666171206144045] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 08/21/2017] [Accepted: 11/28/2017] [Indexed: 01/20/2023] Open
Abstract
Background: Open Angle Glaucoma (POAG) is the leading causes of irreversible blindness worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma; however, a subset of patients experiences a progression of the disease even in presence of normal intraocular pressure values. This implies that risk factors other than intraocular pressure are involved in the pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases such as Alzheimer Disease has been suggested. In this regard, we recently described a high prevalence of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3, in a group of patients with Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among Alzheimer Disease patients. Methods: In this paper researches related to glaucoma and Alzheimer disease are reviewed. Results: Diseases characteristics, i.e. common features, risk factors and pathophysiological mechanisms gathered in the recent literature do suggest that Alzheimer Disease and glaucoma can be considered both age-related neurodegenerative diseases that may co-exist in the elderly. Conclusion: In conclusion, preclinical and clinical evidence gathered so far support the notion that glaucoma is a widespread neurodegenerative condition whose common pathogenetic mechanisms with other diseases, i.e. Alzheimer Disease, should be further investigated as they may shed new light on these diseases improving both diagnosis and treatments.
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Affiliation(s)
- Raffaele Mancino
- Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Alessio Martucci
- Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Massimo Cesareo
- Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Clarissa Giannini
- Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | | | - Giacinto Bagetta
- Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, 87036 Rende, Italy
| | - Carlo Nucci
- Ophthalmology Unit, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
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38
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Anterior Chamber Flare as an Objective and Quantitative Noninvasive Method for Oculopathy in Transthyretin V30M Amyloidosis Patients. J Ophthalmol 2018; 2018:3727543. [PMID: 30327725 PMCID: PMC6171253 DOI: 10.1155/2018/3727543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 08/17/2018] [Indexed: 11/24/2022] Open
Abstract
Purpose Assess the aqueous humor flare in transthyretin V30M amyloidosis patients (ATTRV30M). Materials and Methods This is a retrospective, cross-sectional, noninterventional comparative study including 28 ATTRV30M patients with a unilateral scalloped iris. For comparative analysis, the fellow eye, the nonscalloped iris eye, from each patient was used as control. All patients underwent aqueous humor flare meter and intraocular pressure (IOP) measurements. Results Mean aqueous humor flare was significantly higher in the eyes with the scalloped iris than the control group with the nonscalloped iris (14.1 ± 2.2 versus 6.5 ± 0.9 pc/ms, respectively). No significant differences in IOP were found in the scalloped iris eyes than those in the nonscalloped iris control group (17.1 ± 0.8 versus 16.8 ± 0.7 mmHg, respectively). No significant correlation was not found between the flare and the IOP value within groups. Conclusions In this study, aqueous humor flare values in the scalloped iris eyes may be a valid marker for controlling the stage of the oculopathy in ATTRV30M patients.
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39
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Colligris P, Perez de Lara MJ, Colligris B, Pintor J. Ocular Manifestations of Alzheimer's and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer's Disease. J Ophthalmol 2018; 2018:8538573. [PMID: 30151279 PMCID: PMC6091327 DOI: 10.1155/2018/8538573] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/07/2018] [Accepted: 06/26/2018] [Indexed: 12/20/2022] Open
Abstract
Dementia, including Alzheimer's disease (AD), is a major disorder, leading to several ocular manifestations amongst the elderly population. These visual disorders may be due to retinal nerve degenerative changes, including nerve fibre layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. There is no cure for Alzheimer's, but medicines can slow down the development of many of the classic symptoms, such as loss of memory and communication skills, mood swings, and depression. The disease diagnosis is difficult, and it is only possible through PET scans of the brain, detecting evidence of the accumulation of amyloid and tau. PET is expensive and invasive, requiring the injection of radioactive tracers, which bind with these proteins and glow during scanning. Recently, scientists developed promising eye-scan techniques that may detect Alzheimer's disease at its earliest stage, before major symptoms appear, leading to improved management of the disease symptoms. In this review, we are discussing the visual abnormalities of Alzheimer's and other neurodegenerative diseases, focused on ocular functional-visual-structural biomarkers, retinal pathology, and potential novel diagnostic tools.
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Affiliation(s)
- Pade Colligris
- Universidad Alfonso X, Madrid, Spain
- Ocupharm Diagnostics SL, Madrid, Spain
| | | | - Basilio Colligris
- Ocupharm Diagnostics SL, Madrid, Spain
- Universidad Complutense de Madrid, Madrid, Spain
| | - Jesus Pintor
- Ocupharm Diagnostics SL, Madrid, Spain
- Universidad Complutense de Madrid, Madrid, Spain
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40
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41
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Ishikawa M, Yoshitomi T, Covey DF, Zorumski CF, Izumi Y. Neurosteroids and oxysterols as potential therapeutic agents for glaucoma and Alzheimer's disease. ACTA ACUST UNITED AC 2018; 8:344-359. [PMID: 30774720 DOI: 10.4172/neuropsychiatry.1000356] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Glaucoma is one of the most frequent causes of visual impairment worldwide and involves selective damage to retinal ganglion cells (RGCs) resulting in degeneration of neural pathways connecting retina to visual cortex. It is of interest that similarities in pathological changes have been described in Alzheimer's disease (AD), the most common cause of progressive memory loss and dementia in older people. Accumulation of amyloid-beta (Abeta) and hyperphosphorylated tau is thought to contribute to apoptotic neuronal death in Alzheimer's disease, and similar changes have been linked to apoptotic RGC death in glaucoma. Both glaucoma and Alzheimer's disease also suffer from a lack of effective treatments prompting a search for novel therapeutic interventions. Neurosteroids (NSs) (including oxysterols) are endogenous molecules synthesized in the nervous system from cholesterol that can modulate glutamate and GABA receptors, the primary mediators of fast excitatory and inhibitory neurotransmission in the brain, respectively. Because changes in the glutamate and GABA neurotransmitter systems contribute to the pathogenesis of AD and glaucoma, NSs are possible therapeutic targets for these disorders. In this review, we present recent evidence supporting pathological links between Alzheimer's disease and glaucoma, and focus on the possible role of NSs in these diseases and how NSs might be developed for therapeutic purposes.
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Affiliation(s)
- Makoto Ishikawa
- Department of Ophthalmology, Akita University Graduate School of Medicine, Akita, Japan
| | - Takeshi Yoshitomi
- Department of Ophthalmology, Akita University Graduate School of Medicine, Akita, Japan
| | - Douglas F Covey
- Department of Developmental Biology, Akita University Graduate School of Medicine, Akita, Japan.,Taylor Family Institute for Innovative Psychiatric Research, Akita University Graduate School of Medicine, Akita, Japan
| | - Charles F Zorumski
- Taylor Family Institute for Innovative Psychiatric Research, Akita University Graduate School of Medicine, Akita, Japan.,Center for Brain Research in Mood Disorders, Akita University Graduate School of Medicine, Akita, Japan.,Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O, USA
| | - Yukitoshi Izumi
- Taylor Family Institute for Innovative Psychiatric Research, Akita University Graduate School of Medicine, Akita, Japan.,Center for Brain Research in Mood Disorders, Akita University Graduate School of Medicine, Akita, Japan.,Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O, USA
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42
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Mirzaei M, Gupta VB, Chick JM, Greco TM, Wu Y, Chitranshi N, Wall RV, Hone E, Deng L, Dheer Y, Abbasi M, Rezaeian M, Braidy N, You Y, Salekdeh GH, Haynes PA, Molloy MP, Martins R, Cristea IM, Gygi SP, Graham SL, Gupta VK. Age-related neurodegenerative disease associated pathways identified in retinal and vitreous proteome from human glaucoma eyes. Sci Rep 2017; 7:12685. [PMID: 28978942 PMCID: PMC5627288 DOI: 10.1038/s41598-017-12858-7] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 09/14/2017] [Indexed: 12/05/2022] Open
Abstract
Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis. About 5000 proteins were quantified from retinal tissue and vitreous fluid of glaucoma and control eyes. Of the differentially regulated proteins, 122 were found linked with pathophysiology of Alzheimer’s disease (AD). Pathway analyses of differentially regulated proteins indicate defects in mitochondrial oxidative phosphorylation machinery. The classical complement pathway associated proteins were activated in the glaucoma samples suggesting an innate inflammatory response. The majority of common differentially regulated proteins in both tissues were members of functional protein networks associated brain changes in AD and other chronic degenerative conditions. Identification of previously reported and novel pathways in glaucoma that overlap with other CNS neurodegenerative disorders promises to provide renewed understanding of the aetiology and pathogenesis of age related neurodegenerative diseases.
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Affiliation(s)
- Mehdi Mirzaei
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia. .,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. .,Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia.
| | - Veer B Gupta
- School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Joel M Chick
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Todd M Greco
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
| | - Yunqi Wu
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nitin Chitranshi
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Roshana Vander Wall
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Eugene Hone
- School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Liting Deng
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
| | - Yogita Dheer
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mojdeh Abbasi
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mahdie Rezaeian
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Yuyi You
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, Sydney University, Sydney, NSW, Australia
| | - Ghasem Hosseini Salekdeh
- Department of Molecular Systems Biology, Cell Science Research Center, Royan, Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Paul A Haynes
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
| | - Mark P Molloy
- Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.,Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW, Australia
| | - Ralph Martins
- School of Medical Sciences, Edith Cowan University, Joondalup, WA, Australia.,Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Ileana M Cristea
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
| | - Steven P Gygi
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA
| | - Stuart L Graham
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Save Sight Institute, Sydney University, Sydney, NSW, Australia
| | - Vivek K Gupta
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
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Boucard CC, Hanekamp S, Ćurčić-Blake B, Ida M, Yoshida M, Cornelissen FW. Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma. Ophthalmic Physiol Opt 2017; 36:344-53. [PMID: 27112227 DOI: 10.1111/opo.12297] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 03/07/2016] [Indexed: 11/25/2022]
Abstract
PURPOSE Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma. METHODS We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage. RESULTS Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p < 0.05; family-wise error-corrected) comprising fibres of both the optic radiation and the forceps major. Additional analysis confirmed bilateral involvement of the optic radiations and forceps major and additionally revealed damage to the corpus callosum and parietal lobe (p < 0.09; family-wise error-corrected). The region of interest-based analysis revealed a positive association between Fractional Anisotropy of the optic radiation and optic nerve damage. CONCLUSIONS In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.
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Affiliation(s)
- Christine C Boucard
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
| | - Sandra Hanekamp
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, The Netherlands
| | - Branislava Ćurčić-Blake
- Department of Neuroscience, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Masahiro Ida
- Department of Radiology, Tokyo Metropolitan Health and Medical Treatment Corporation, Ebara Hospital, Tokyo, Japan
| | - Masaki Yoshida
- Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan
| | - Frans W Cornelissen
- Laboratory for Experimental Ophthalmology, University Medical Center Groningen, University of Groningen, The Netherlands
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Funke S, Perumal N, Bell K, Pfeiffer N, Grus FH. The potential impact of recent insights into proteomic changes associated with glaucoma. Expert Rev Proteomics 2017; 14:311-334. [PMID: 28271721 DOI: 10.1080/14789450.2017.1298448] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Glaucoma, a major ocular neuropathy, is still far from being understood on a molecular scale. Proteomic workflows revealed glaucoma associated alterations in different eye components. By using state-of-the-art mass spectrometric (MS) based discovery approaches large proteome datasets providing important information about glaucoma related proteins and pathways could be generated. Corresponding proteomic information could be retrieved from various ocular sample species derived from glaucoma experimental models or from original human material (e.g. optic nerve head or aqueous humor). However, particular eye tissues with the potential for understanding the disease's molecular pathomechanism remains underrepresented. Areas covered: The present review provides an overview of the analysis depth achieved for the glaucomatous eye proteome. With respect to different eye regions and biofluids, proteomics related literature was found using PubMed, Scholar and UniProtKB. Thereby, the review explores the potential of clinical proteomics for glaucoma research. Expert commentary: Proteomics will provide important contributions to understanding the molecular processes associated with glaucoma. Sensitive discovery and targeted MS approaches will assist understanding of the molecular interplay of different eye components and biofluids in glaucoma. Proteomic results will drive the comprehension of glaucoma, allowing a more stringent disease hypothesis within the coming years.
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Affiliation(s)
- Sebastian Funke
- a Experimental Ophthalmology , University Medical Center , Mainz , Germany
| | - Natarajan Perumal
- a Experimental Ophthalmology , University Medical Center , Mainz , Germany
| | - Katharina Bell
- a Experimental Ophthalmology , University Medical Center , Mainz , Germany
| | - Norbert Pfeiffer
- a Experimental Ophthalmology , University Medical Center , Mainz , Germany
| | - Franz H Grus
- a Experimental Ophthalmology , University Medical Center , Mainz , Germany
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Nucci C, Russo R, Martucci A, Giannini C, Garaci F, Floris R, Bagetta G, Morrone LA. New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system. Eur J Pharmacol 2016; 787:119-26. [DOI: 10.1016/j.ejphar.2016.04.030] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 03/23/2016] [Accepted: 04/14/2016] [Indexed: 01/30/2023]
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Williams PA, Tribble JR, Pepper KW, Cross SD, Morgan BP, Morgan JE, John SWM, Howell GR. Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma. Mol Neurodegener 2016; 11:26. [PMID: 27048300 PMCID: PMC4822272 DOI: 10.1186/s13024-016-0091-6] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 03/23/2016] [Indexed: 12/13/2022] Open
Abstract
Background Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases. Results Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa-/- mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture. Conclusions This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.
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Affiliation(s)
| | - James R Tribble
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | | | - Stephen D Cross
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - B Paul Morgan
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - James E Morgan
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Simon W M John
- The Jackson Laboratory, Bar Harbor, ME, 04609, USA. .,Department of Ophthalmology, Tufts University of Medicine, Boston, MA, 02111, USA. .,The Howard Hughes Medical Institute, Bar Harbor, ME, 04609, USA.
| | - Gareth R Howell
- The Jackson Laboratory, Bar Harbor, ME, 04609, USA. .,Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, Boston, MA, USA.
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Pepple KL, Rotkis L, Wilson L, Sandt A, Van Gelder RN. Comparative Proteomic Analysis of Two Uveitis Models in Lewis Rats. Invest Ophthalmol Vis Sci 2016; 56:8449-56. [PMID: 26747776 DOI: 10.1167/iovs.15-17524] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE Inflammation generates changes in the protein constituents of the aqueous humor. Proteins that change in multiple models of uveitis may be good biomarkers of disease or targets for therapeutic intervention. The present study was conducted to identify differentially-expressed proteins in the inflamed aqueous humor. METHODS Two models of uveitis were induced in Lewis rats: experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU). Differential gel electrophoresis was used to compare naïve and inflamed aqueous humor. Differentially-expressed proteins were separated by using 2-D gel electrophoresis and excised for identification with matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF). Expression of select proteins was verified by Western blot analysis in both the aqueous and vitreous. RESULTS The inflamed aqueous from both models demonstrated an increase in total protein concentration when compared to naïve aqueous. Calprotectin, a heterodimer of S100A8 and S100A9, was increased in the aqueous in both PMU and EAU. In the vitreous, S100A8 and S100A9 were preferentially elevated in PMU. Apolipoprotein E was elevated in the aqueous of both uveitis models but was preferentially elevated in EAU. Beta-B2-crystallin levels decreased in the aqueous and vitreous of EAU but not PMU. CONCLUSIONS The proinflammatory molecules S100A8 and S100A9 were elevated in both models of uveitis but may play a more significant role in PMU than EAU. The neuroprotective protein β-B2-crystallin was found to decline in EAU. Therapies to modulate these proteins in vivo may be good targets in the treatment of ocular inflammation.
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Abstract
Glaucoma is a group of optic neuropathies that is more prevalent among the elderly population and commonly associates with comorbidities, including mental disorders in that population. This article reviews the relationship between glaucoma and mental disorders. In it, we discuss the coexistence of glaucoma and mental illnesses, including Alzheimer's disease, depression, and personality disorder. We also focus on the proper treatment approaches for glaucoma patients with mental comorbidity and poor treatment adherence. We summarize some cautiously recommended psychotherapeutic medications, while also discussing the psychologically adverse effects of antiglaucoma medications.
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Prins D, Hanekamp S, Cornelissen FW. Structural brain MRI studies in eye diseases: are they clinically relevant? A review of current findings. Acta Ophthalmol 2016; 94:113-21. [PMID: 26361248 DOI: 10.1111/aos.12825] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 07/09/2015] [Indexed: 01/10/2023]
Abstract
Many eye diseases reduce visual acuity or are associated with visual field defects. Because of the well-defined retinotopic organization of the connections of the visual pathways, this may affect specific parts of the visual pathways and cortex, as a result of either deprivation or transsynaptic degeneration. For this reason, over the past several years, numerous structural magnetic resonance imaging (MRI) studies have examined the association of eye diseases with pathway and brain changes. Here, we review structural MRI studies performed in human patients with the eye diseases albinism, amblyopia, hereditary retinal dystrophies, age-related macular degeneration (AMD) and glaucoma. We focus on two main questions. First, what have these studies revealed? Second, what is the potential clinical relevance of their findings? We find that all the aforementioned eye diseases are indeed associated with structural changes in the visual pathways and brain. As such changes have been described in very different eye diseases, in our view the most parsimonious explanation is that these are caused by the loss of visual input and the subsequent deprivation of the visual pathways and brain regions, rather than by transsynaptic degeneration. Moreover, and of clinical relevance, for some of the diseases - in particular glaucoma and AMD - present results are compatible with the view that the eye disease is part of a more general neurological or neurodegenerative disorder that also affects the brain. Finally, establishing structural changes of the visual pathways has been relevant in the context of new therapeutic strategies to restore retinal function: it implies that restoring retinal function may not suffice to also effectively restore vision. Future structural MRI studies can contribute to (i) further establish relationships between ocular and neurological neurodegenerative disorders, (ii) investigate whether brain degeneration in eye diseases is reversible, (iii) evaluate the use of neuroprotective medication in ocular disease, (iv) determine optimal timing for retinal implant insertion and (v) establish structural MRI examination as a diagnostic tool in ophthalmology.
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Affiliation(s)
- Doety Prins
- Laboratory of Experimental Ophthalmology; University of Groningen; University Medical Center Groningen; Groningen the Netherlands
| | - Sandra Hanekamp
- Laboratory of Experimental Ophthalmology; University of Groningen; University Medical Center Groningen; Groningen the Netherlands
| | - Frans W. Cornelissen
- Laboratory of Experimental Ophthalmology; University of Groningen; University Medical Center Groningen; Groningen the Netherlands
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Abstract
Exfoliation syndrome (XFS) is an age-related disease characterized by the production, deposition, and progressive accumulation of a white, fibrillar, extracellular material in many ocular tissues, most prominent on the anterior lens surface and pupillary border. Its prevalence increases steadily with age in all populations. It is the most common identifiable cause of open-angle glaucoma worldwide and is a potentially reversible or even curable disease. First described in Finland in 1917 by Lindberg, it has long been associated with open-angle glaucoma. However, in recent years, it is being increasingly reported in conjunction with a multiplicity of both ocular and systemic disorders, and the number of these is expected to grow, particularly with investigations based on attempts to associate other diseases with those genes known to be associated with XFS. Despite the focus on XFS as a cause of open-angle glaucoma for nearly a century, in reality it is still only an ocular manifestation of a protean systemic disease. It is a unique disorder with extensive and often serious ocular and systemic manifestations and not, as it has long been termed, a "form" or "type" of glaucoma. This misconception has delayed research into the molecular and cellular processes involved in its development, and the underestimation of its overall importance and its underlying causative mechanisms have largely been long ignored. The purpose of this article is to review the systemic disorders which are becoming increasingly associated with XFS. Reviews of epidemiology, genetics, biomarkers, molecular mechanisms of development, and ocular findings may be found elsewhere.
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Affiliation(s)
- Robert Ritch
- From the Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY
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