Stress, Allostatic Load, and Neuroinflammation: Implications for Racial and Socioeconomic Health Disparities in Glaucoma

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TL;DR

This narrative review synthesizes evidence that chronic stress and allostatic load contribute to glaucoma pathogenesis through glucocorticoid-mediated neuroinflammation, mitochondrial dysfunction, and neurovascular dysregulation, independent of intraocular pressure. The authors propose that these stress-related mechanisms may help explain the disproportionate burden of glaucoma in African-ancestry and lower socioeconomic populations. The clinical significance lies in identifying novel therapeutic targets beyond IOP-lowering and highlighting the need for interdisciplinary approaches addressing social determinants of health.

Full summary

4,229 CHARS

**Background:** Glaucoma is the leading cause of irreversible blindness worldwide, with nearly 100 million people projected to be affected by 2040. While elevated intraocular pressure (IOP) is a major risk factor, approximately 40% of patients experience disease progression despite IOP-lowering therapy, and a subset (normal-tension glaucoma, NTG) develops progressive retinal ganglion cell (RGC) degeneration without elevated IOP. This suggests non-IOP mechanisms, including neuroinflammation, are critical. Chronic stress and allostatic load—the cumulative 'wear and tear' from repeated stress responses—have been implicated in neurodegenerative diseases, but their role in glaucoma is less understood. This review examines the molecular, cellular, and systemic pathways linking stress, neuroinflammation, and glaucoma, and explores how these mechanisms may underlie racial and socioeconomic disparities.

**Methods:** This is a narrative review synthesizing evidence from preclinical studies, clinical trials, epidemiological studies, and reviews published up to 2023. The authors searched for literature on glucocorticoid signaling, microglial activation, HPA-axis dysregulation, mitochondrial dysfunction, neurovascular dysregulation, diabetes, psychosocial stress, allostatic load, and health disparities in glaucoma. Key studies cited include the Trier Social Stress Test (TSST) experiments, NHANES cohort analyses, genome-wide association studies (e.g., POAAGG), and case-control studies on NTG and Flammer syndrome.

**Key Results:** The review identifies several interconnected pathways: (1) Glucocorticoid-mediated microglial activation: Stress activates the HPA axis, releasing glucocorticoids that push microglia toward a proinflammatory M1 phenotype, creating a self-reinforcing cycle of neuroinflammation. (2) Mitochondrial allostatic load: Chronic stress induces mitochondrial dysfunction in RGCs, leading to oxidative stress and inflammation. (3) Neurovascular dysregulation: Stress-induced autonomic dysfunction impairs ocular blood flow autoregulation, contributing to ischemic optic neuropathy, particularly in NTG. (4) Diabetes and vascular inflammation: Hyperglycemia from stress-induced glucocorticoid release exacerbates endothelial dysfunction and microglial activation, linking diabetes to glaucoma. (5) Psychosocial stress and IOP: A small TSST study (N=28) showed a mean IOP elevation >1 mmHg after acute stress, with elevated salivary cortisol and heart rate. Another TSST study found an inverse relationship between baseline ACTH and retinal nerve fiber layer thickness (p=0.009 globally). (6) Allostatic load: In the NHANES cohort, visual acuity impairment was associated with increased allostatic load (p=0.01), and non-Hispanic Black ethnicity was a risk factor for elevated allostatic load (p<0.01). (7) Socioeconomic disparities: Lower income and education are associated with higher glaucoma burden; in the KNHANES study (N>24,000), odds of glaucoma decreased with increasing income. (8) Racial disparities: African-ancestry individuals have higher glaucoma prevalence and severity, with evidence of greater retinal avascular area and genetic variants (e.g., three causal variants identified in a GWAS of African-ancestry cohorts). Allostatic load scores are higher in African Americans even after controlling for SES, and experiences of racial discrimination are associated with higher allostatic load.

**Clinical Implications:** This review provides a comprehensive framework linking chronic stress, neuroinflammation, and glaucoma, suggesting that interventions targeting stress reduction, HPA-axis modulation, and neuroinflammation (e.g., minocycline, which reversed M1 microglial response in an animal model) could complement IOP-lowering therapies. The allostatic load hypothesis offers a mechanistic explanation for health disparities, emphasizing the need for interdisciplinary approaches that address social determinants of health, improve access to care, and reduce systemic inequalities. Future research should focus on developing risk models incorporating multi-level factors (genetic, psychosocial, environmental) and testing stress-mitigation strategies in glaucoma management.