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Lessons from glaucoma: rethinking the fluid-brain barriers in common neurodegenerative disorders.

ABSTRACT: Glaucoma has been recently characterized as a member of the group of anoikis-related diseases. Anoikis, a form of apoptosis, can be triggered by the unfastening of adherent junctions present in astrocytes. In those areas of the central nervous system in which the soma of the neurons or their axons and dendrites are metabolically dependent on the activity of astrocytes, a derangement of the lactate shuttle caused by a separation between the plasma membranes of neurons and astrocytes would result in metabolic impairment of the neurons themselves. In glaucoma, the triggering event has been attributed to the posterior deviation of aqueous humor towards the astrocyte-rich prelaminar tissue of the optic nerve head. The mean calcium content in the aqueous is able to interfere with calcium-dependent adherent junctions and induce anoikis of the astrocytes. As the cerebrospinal fluid has a similar base calcium concentration, a shunt of cerebrospinal fluid through the cerebral parenchyma would be able to interfere in the astrocytic architecture with dire consequences to the metabolically dependent neurons. Here the similitude between glaucoma, amyotrophic lateral sclerosis and Alzheimer's disease are discussed and the concept of the break in the fluid-brain barrier, as an event separated from the blood-brain barrier, is stressed.

SUBMITTER: Carreras FJ

PROVIDER: S-EPMC6404483 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Lessons from glaucoma: rethinking the fluid-brain barriers in common neurodegenerative disorders.

Carreras Francisco Javier FJ

Neural regeneration research 20190601 6

Glaucoma has been recently characterized as a member of the group of anoikis-related diseases. Anoikis, a form of apoptosis, can be triggered by the unfastening of adherent junctions present in astrocytes. In those areas of the central nervous system in which the soma of the neurons or their axons and dendrites are metabolically dependent on the activity of astrocytes, a derangement of the lactate shuttle caused by a separation between the plasma membranes of neurons and astrocytes would result ...[more]

PMID: 30762000

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Project description:BackgroundPrimary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive.MethodIn this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders.FindingsThis study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma.InterpretationOur findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits.FundingPG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEIEY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.

Project description:PurposeTo evaluate the frequency of 11 commonly cited barriers to optimal glaucoma medication adherence among glaucoma patients and to identify barriers contributing to poor adherence.DesignProspective, cross-sectional survey.ParticipantsOne hundred ninety adults with glaucoma taking 1 or more glaucoma medication who received care in glaucoma clinics in Ann Arbor, Michigan, and Baltimore, Maryland.MethodsParticipants completed a survey on demographic and disease characteristics, barriers to optimal glaucoma medication adherence, interest in an eye drop aid, and self-reported adherence (measured by the Morisky Adherence Scale). Descriptive statistics and logistic regression analyses were performed.Main outcome measuresFrequency and number of barriers to adherence among both adherent and nonadherent patients. Odds ratios (ORs) with 95% confidence intervals (CIs) identifying barriers associated with poor adherence.ResultsTwenty-seven percent of the sample reported poor adherence. Sixty-one percent of all participants cited multiple barriers and 10% cited a single barrier as impediments to optimal adherence. Twenty-nine percent of subjects cited no barriers, although only 13% of patients who cited no barriers were nonadherent. Among nonadherent patients, 31% or more cited each of the 11 barriers as important. Logistic regression analysis, adjusted for age, revealed that the following barriers were associated with higher odds of nonadherence: decreased self-efficacy (OR, 4.7; 95% CI, 2.2-9.7; P ≤ 0.0001), difficulty instilling drops (OR, 2.3; 95% CI, 1.1-4.9; P = 0.03), forgetfulness (OR, 5.6; 95% CI, 2.6-12.1; P ≤ 0.0001), and difficulties with the medication schedule (OR, 2.9; 95% CI, 1.4-6.0; P = 0.006). For each additional barrier cited as important, there was a 10% increased odds of being nonadherent (OR, 1.1; 95% CI, 1.0-1.2; P = 0.01).ConclusionsEach of the 11 barriers was important to at least 30% of surveyed patients with poor adherence, with most identifying multiple barriers to adherence. Low self-efficacy, forgetfulness, and difficulty with drop administration and the medication schedule were barriers associated with poor adherence. Interventions to improve medication adherence must address each patient's unique set of barriers.

Project description:In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

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Lessons from glaucoma: rethinking the fluid-brain barriers in common neurodegenerative disorders.

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Lessons from glaucoma: rethinking the fluid-brain barriers in common neurodegenerative disorders.

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