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Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

ABSTRACT: Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry-based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM and MH to identify the key proteins, as well as the multiple interconnected biochemical pathways, contributing to the development of these diseases. We identified a total of 1,014 unique proteins, many of which are linked to inflammation and the complement cascade, revealing the inflammation processes in retinal diseases. Additionally, we detected a profound difference in the proteomes of iEMR and MH compared to those of diabetic retinopathy with macular edema and rhegmatogenous retinal detachment. A large number of neuronal proteins were present at higher levels in the iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins, and signaling molecules, pointing toward the important role of neurodegenerative component in the pathogenesis of age-related vitreoretinal diseases. Despite them having marked similarities, several unique vitreous proteins were identified in both iERM and MH, from which candidate targets for new diagnostic and therapeutic approaches can be provided.

SUBMITTER: Ohman T

PROVIDER: S-EPMC6156470 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

Öhman Tiina T Tamene Fitsum F Göös Helka H Loukovaara Sirpa S Varjosalo Markku M

Aging cell 20180702 5

Aging is a phenomenon that is associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. iERM is characterized by fibrous tissue developing on the surface of the macula, which leads to biomechanical and biochemical macular damage. MH is a small breakage in the macula and is associated with ma ...[more]

PMID: 29963742

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Project description:IntroductionEstablishing efficacy of and molecular pathways for statins has the potential to impact incidence of Alzheimer's and age-related neurodegenerative diseases (NDD).MethodsThis retrospective cohort study surveyed US-based Humana claims, which includes prescription and patient records from private-payer and Medicare insurance. Claims from 288,515 patients, aged 45 years and older, without prior history of NDD or neurological surgery, were surveyed for a diagnosis of NDD starting 1 year following statin exposure. Patients were required to be enrolled with claims data for at least 6 months prior to first statin prescription and at least 3 years thereafter. Computational system biology analysis was conducted to determine unique target engagement for each statin.ResultsOf the 288,515 participants included in the study, 144,214 patients (mean [standard deviation (SD)] age, 67.22 [3.8] years) exposed to statin therapies, and 144,301 patients (65.97 [3.2] years) were not treated with statins. The mean (SD) follow-up time was 5.1 (2.3) years. Exposure to statins was associated with a lower incidence of Alzheimer's disease (1.10% vs 2.37%; relative risk [RR], 0.4643; 95% confidence interval [CI], 0.44-0.49; P < .001), dementia 3.03% vs 5.39%; RR, 0.56; 95% CI, 0.54-0.58; P < .001), multiple sclerosis (0.08% vs 0.15%; RR, 0.52; 95% CI, 0.41-0.66; P < .001), Parkinson's disease (0.48% vs 0.92%; RR, 0.53; 95% CI, 0.48-0.58; P < .001), and amyotrophic lateral sclerosis (0.02% vs 0.05%; RR, 0.46; 95% CI, 0.30-0.69; P < .001). All NDD incidence for all statins, except for fluvastatin (RR, 0.91; 95% CI, 0.65-1.30; P = 0.71), was reduced with variances in individual risk profiles. Pathway analysis indicated unique and common profiles associated with risk reduction efficacy.DiscussionBenefits and risks of statins relative to neurological outcomes should be considered when prescribed for at-risk NDD populations. Common statin activated pathways indicate overarching systems required for risk reduction whereas unique targets could advance a precision medicine approach to prevent neurodegenerative diseases.

Project description:BACKGROUND:Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE:To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS:We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ?CVF. Based on ?CVF, subjects were split into absolute or quartile groups. Student's t test, ?2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS:No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ?CVF had higher disability scores (p?=?0.013), lower gray matter (p?=?0.039) and cortical (p?=?0.044) volumes. The negative ?CVF MS group also showed numerically worse bladder/bowel function when compared to the positive ?CVF (2.3 vs. 1.5, p?=?0.052). Similarly, the lowest quartile ?CVF MS group had higher T1-lesion volumes (p?=?0.033), T2-lesion volumes (p?=?0.032), and lower deep gray matter (p?=?0.043) and thalamus (p?=?0.033) volumes when compared to those with higher ?CVF quartiles. CONCLUSION:No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ?CVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

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Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

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Systems pathology analysis identifies neurodegenerative nature of age-related vitreoretinal interface diseases.

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