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Molecular and epidemiological studies on eyes with pseudoexfoliation syndrome
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology. (Per Söderberg)ORCID iD: 0000-0002-9938-2808
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pseudoexfoliation (PEX) syndrome is an age-related condition characterized by the production and accumulation of extracellular fibrillary material in the anterior segment of the eye. PEX predisposes for several pathological conditions, such as glaucoma and complications during and after cataract surgery. The pathogenesis of PEX is not yet fully understood. It is multifactorial with genetics and ageing as contributing factors.

We aimed to study the proteome in aqueous humor (AH) in PEX in order to increase the knowledge about its pathophysiology. Therefore, we developed sampling techniques and evaluated separation methods necessary for analyzing small sample volumes. Other objectives were to study the lens capsule in eyes with PEX regarding small molecules, and to investigate the association between PEX and cataract surgery in a population-based 30-year follow-up study.

Samples of AH from eyes with PEX and control eyes were collected during cataract surgery. In pooled, and individual samples, various liquid based separation techniques and high resolution mass spectrometry were utilized. For quantitation, various methods for labeling, and label free techniques were applied. Lens capsules were collected from some of the patients, and analysed by imaging mass spectrometry. A cohort of 1,471 elderly individuals underwent a comprehensive ophthalmological examination at baseline. Medical information was obtained by questionnaires, and from medical records. Incident cases of cataract surgery were identified by review of medical records.

In the initial study, several techniques were explored for protein detection, and a number of proteins were identified as differentially expressed. In the individually labelled samples, changes in the proteome were observed. Eyes with PEX contained higher levels of proteins involved in inflammation, oxidative stress, and coagulation, suggesting that these mechanisms are involved in the pathogenesis in PEX. The levels of β/γ-crystallins were significantly increased in PEX, which is a novel finding. In the lens capsules from individuals with PEX, changes in the lipid composition was observed with time-of-flight secondary ion mass spectrometry. These changes remain to be elucidated. By multivariate analysis, lens opacities were the first, and PEX the second most important predictor for cataract surgery, the later accounting for a 2.38-fold increased risk for cataract surgery.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1130
Keyword [en]
Pseduoexfoliation syndrome, PEX, aqueous humor, cataract, cataract surgery, lens capsule, proteomics, mass spectrometry, MS, MALDI TOF MS/MS, quantitative proteomics, iTRAQ, dimethyl labeling, imaging mass spectrometry, IMS, time of flight secondary ion mass spectrometry, TOF-SIMS, crystallin, epidemiology, risk factor
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
URN: urn:nbn:se:uu:diva-260714ISBN: 978-91-554-9312-7 (print)OAI: oai:DiVA.org:uu-260714DiVA: diva2:849028
Public defence
2015-10-15, Fåhreussalen,ingång C5, Rudbecklaboratoriet, Akademiska sjukhuset, Dag Hammarskjölds väg 20, 751 85 Uppsala, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-09-24 Created: 2015-08-24 Last updated: 2015-10-01
List of papers
1. Protein content in aqueous humor from patients with pseudoexfoliation (PEX) investigated by capillary-LC MALDI-TOF/TOF MS
Open this publication in new window or tab >>Protein content in aqueous humor from patients with pseudoexfoliation (PEX) investigated by capillary-LC MALDI-TOF/TOF MS
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2009 (English)In: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 3, no 3, 299-306 p.Article in journal (Refereed) Published
Abstract [en]

Analysis of proteins in human body fluids is challenging since the composition of the sample often is rather complex. Here we present a method for analysis of proteins in aqueous humor from two groups of cataract patients, with and without pseudoexfoliation (PEX). Aqueous humor is an extracellular fluid contained in the anterior chamber of the eye between the cornea and iris. The limited volume of sample requires sophisticated analysis techniques. Our method is based on a total tryptic digestion of the sample followed by capillary LC-MALDI MS and MS/MS analysis of the peptides. The method is rapid, efficient and suitable as a complement or alternative to more commonly used methods based on gel electrophoretic experiments. With this method we found and unambiguously identified 30 nonredundant proteins. Proteins found include general transport proteins such as albumin and apolipoprotein A1 but also specific proteins involved in immune response, such as   complement factors. Cystatin C, clusterin, and crystallins were also found. Although the number of proteins was roughly the same in both groups there was a significant difference in their identities. These findings may give some new insights into the pathophysiology of the PEX syndrome.

Keyword
Aqueous humor, Capillary liquid chromatography, Human body fluids, MALDI-TOF MS/MS, Pseudoexfoliation syndrome
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97814 (URN)10.1002/prca.200780077 (DOI)000264794700002 ()
Available from: 2008-11-20 Created: 2008-11-20 Last updated: 2017-12-14Bibliographically approved
2. Proteins in aqueous humor from cataract patients with and without pseudoexfoliation syndrome
Open this publication in new window or tab >>Proteins in aqueous humor from cataract patients with and without pseudoexfoliation syndrome
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2012 (English)In: European journal of mass spectrometry, ISSN 1469-0667, E-ISSN 1751-6838, Vol. 18, no 6, 531-541 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the protein content in aqueous humor in eyes with and without pseudoexfoliations (PEX) and to evaluate the quantitative proteomics method, isobaric tagging for relative and absolute protein quantification (iTRAQ), in combination with two separation methods followed by matrix-assisted Laser desorption/ionization (MALDI) mass spectrometry and tandem mass spectrometry (MS/MS). During cataract surgery, samples of aqueous humor were collected from 20 eyes with PEX and from 18 control eyes. The relative concentrations of proteins in the pooled samples of ten PEX eyes and eight controls were evaluated after trypsin digestion and labeling of the peptides with (iTRAQ) reagent. Two separation methods, Liquid chromatography (LC) and capillary electrophoresis (CE) were used, followed by MALDI mass spectrometry and MS/MS. Furthermore, 1D gel electrophoresis was performed on the remaining ten pooled PEX samples and ten control samples. The gel material was separated by nano-liquid chromatography (nano-LC) followed by Linear-ion-trap quadrupole Fourier transformation ion cyclotron resonance (FT-ICR). Fifty four proteins were identified in the LC runs and 24 with CE. The relative concentrations of beta-crystallines B2 and S were raised and those of angiotensinogen and osteopontin lowered in the PEX sample compared to the control. The trends regarding beta-crystallines B2, angiotensinogen and osteopontin were confirmed by the 1D gel electrophoresis.

Keyword
pseudoexfoliations (PEX), isobaric tagging, protein quantification, proteomics, aqueous humour, osteopontin, angiotensinogen
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-197670 (URN)10.1255/ejms.1208 (DOI)000315745600007 ()
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-12-06Bibliographically approved
3. Proteomic Analysis of the Aqueous Humor in Eyes with Pseudoexfoliation Syndrome
Open this publication in new window or tab >>Proteomic Analysis of the Aqueous Humor in Eyes with Pseudoexfoliation Syndrome
(English)Article in journal (Refereed) Submitted
Keyword
Aqueous humor; Pseudoexfoliation syndrome; Quantitative proteomics; Dimethyl labelling; Mass spectrometry
National Category
Ophthalmology Analytical Chemistry
Research subject
Ophtalmology
Identifiers
urn:nbn:se:uu:diva-260949 (URN)
Available from: 2015-08-26 Created: 2015-08-26 Last updated: 2015-10-01
4. Imaging of Human Lens Capsules with Pseudoexfoliation Syndrome by Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS)
Open this publication in new window or tab >>Imaging of Human Lens Capsules with Pseudoexfoliation Syndrome by Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS)
(English)Manuscript (preprint) (Other academic)
Keyword
PEX, cataract, lens capsule, time of flight secondary mass spectrometry (TOF-SIMS), imaging mass spectrometry (IMS), sphingolipids
National Category
Ophthalmology
Research subject
Ophtalmology; Chemistry with specialization in Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-260946 (URN)
Funder
Swedish Research Council, 621-2011-4423
Available from: 2015-08-26 Created: 2015-08-26 Last updated: 2015-10-01
5. Pseudoexfoliation and cataract surgery: a population-based 30-year follow-up study
Open this publication in new window or tab >>Pseudoexfoliation and cataract surgery: a population-based 30-year follow-up study
2015 (English)In: Acta Ophthalmologica Scandinavica, ISSN 1395-3907, E-ISSN 1600-0420, Vol. 93, no 8, 774-777 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE:

To study the relationship between pseudoexfoliation (PEX) and cataract surgery in a population in which PEX is a common finding.

METHODS:

Survival analyses were performed in a cohort of 760 residents 65-74 years of age, examined in a population survey in the municipality of Tierp, Sweden, during 1984-1986. To expand the cohort, participants in other studies in Tierp were enrolled. Additionally, subjects were recruited by means of glaucoma case records established at the Eye Department in Tierp in 1978-2007. In total, the cohort comprised 1471 individuals, representing more than 15 900 person-years of risk. Information on cataract surgery was obtained from the glaucoma case records and from medical records.

RESULTS:

By the end of the study in August 2014, 564 subjects had undergone cataract surgery. Of these cases, 224 were affected by PEX at baseline. In multivariate analyses, PEX was the second most important predictor for cataract surgery after lens opacities, accounting for a 2.38-fold (95% confidence interval 2.01-2.84) increased risk.

CONCLUSION:

The results strongly suggest that PEX is a predictor for cataract surgery in the population under study.

Place, publisher, year, edition, pages
John Wiley & Sons, 2015
Keyword
cataract, cataract surgery, epidemiology, exfoliation syndrome, pseudoexfoliation, risk factor
National Category
Ophthalmology
Research subject
Ophtalmology
Identifiers
urn:nbn:se:uu:diva-260948 (URN)10.1111/aos12789 (DOI)000367654500034 ()
Available from: 2015-08-26 Created: 2015-08-26 Last updated: 2017-12-04Bibliographically approved

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