https://orcid.org/0000-0003-3187-2410
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Abstract
The brain is the key organ that orchestrates the stress response which translates to the retina. The retina is an extension of the brain and retinal symptoms in subjects with neurodegenerative diseases substantiated the eye as a window to the brain. The retina is used in this study to determine whether chronic stress reflects neurodegenerative signs indicative of neurodegenerative conditions. A three-year prospective cohort (n = 333; aged 46 ± 9 years) was stratified into stress-phenotype cases (n = 212) and controls (n = 121) by applying the Malan stress-phenotype index. Neurodegenerative risk markers included ischemia (astrocytic S100 calcium-binding protein B/S100B); 24-h blood pressure, proteomics; inflammation (tumor-necrosis-factor-α/TNF-α); neuronal damage (neuron-specific-enolase); anti-apoptosis of retinal-ganglion-cells (beta-nerve-growth-factor), astrocytic activity (glial-fibrillary-acidic-protein); hematocrit (viscosity) and retinal follow-up data [vessels; stress-optic-neuropathy]. Stress-optic-neuropathy risk was calculated from two indices: a newly derived diastolic-ocular-perfusion-pressure cut-point ≥68 mmHg relating to the stress-phenotype; combined with an established cup-to-disk ratio cut-point ≥0.3. Higher stress-optic-neuropathy (39% vs. 17%) and hypertension (73% vs. 16%) prevalence was observed in the stress-phenotype cases vs. controls. Elevated diastolic-ocular-perfusion-pressure, indicating hypoperfusion, was related to arterial narrowing and trend for ischemia increases in the stress-phenotype. Ischemia in the stress-phenotype at baseline, follow-up and three-year changes was related to consistent inflammation (TNF-α and cytokine-interleukin-17-receptor-A), neuron-specific-enolase increases, consistent apoptosis (chitinase-3-like protein 1, low beta-nerve-growth-factor), glial-fibrillary-acidic-protein decreases, elevated viscosity, vein widening as risk marker of endothelial dysfunction in the blood-retinal barrier, lower vein count, and elevated stress-optic-neuropathy. The stress-phenotype and related neurodegenerative signs of ongoing brain ischemia, apoptosis and endothelial dysfunction compromised blood–retinal barrier permeability and optic nerve integrity. In fact, the stress-phenotype could identify persons at high risk of neurodegeneration to indicate a neurodegenerative condition.
GRAPHICAL ABSTRACT
Acknowledgements
This study would also not have been possible without all the individuals who voluntarily participated; and the collaborators sponsoring in-kind analyses.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
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Notes on contributors
Leoné Malan
Leoné Malan raised a family before she commenced with research in 2007. She aimed to describe a neurophysiological pathway linking emotional stress to microvascular dysregulation in the brain-heart axis. With this focus in mind, she designed the first psychophysiological prospective cohort study in Sub-Saharan Africa [Sympathetic activity and Ambulatory Blood pressure in Africans/SABPA], which received an international award for project design excellence. She and her husband, Nico Malan, developed a preventive screening tool to determine the risk for chronic stress and stroke to combat neurodegeneration. She delivered 41 Master’s and PhD students and co-authored >180 scientific publications.
Roelof van Wyk
Roelof van Wyk is a clinical ophthalmologist in private practice, located in Potchefstroom in the North-West Province, South Africa. His research interests are the retina and glaucoma. He is an anterior segment and posterior segment Ophthalmic surgeon. He is updated with the latest research and has membership with the European VitreoRetinal Society, the European Society of Retina Specialists and the Ophthalmological Society of South Africa.
Roland von Känel
Roland von Känel is a specialist in psychiatry and psychotherapy and in general internal medicine. Since 2018, he is Director of the Division of Consultant Liaison Psychiatry and Psychosomatic Medicine at the University Hospital Zurich and Chair of Consultant Liaison Psychiatry and Psychosomatic Medicine at the University of Zurich, Switzerland. His clinical focus is on behavioural cardiology and stress-related disorders. His research examines the psychobiological mechanisms linking psychological processes and physical illness, with a particular focus on cardiovascular disease. He has co-authored over 500 scientific articles and book chapters and co-edited two textbooks on psychosomatic medicine.
Tjalf Ziemssen
Tjalf Ziemssen is the Director of the Center of Clinical Neuroscience, and Head of the Autonomic Neuroendocrinological lab (ANF) and multiple sclerosis center. He has been involved with more than >140 interventional and non-interventional studies and delivered > 60 PhD and MD students. He received substantial funds for third-party projects and is the recipient of several awards. He has co-authored over 400 scientific articles.
Walthard Vilser
Dr-Ing Walthard Vilser, is an engineer and specialist in biomedical engineering. He patented, researched and developed with his team the Dynamic Retinal Vessel Analysis. He is the main founder of Imedos and was the managing director until he left the company two years ago. Today he is involved in research work of different international research groups on retinal vessel analysis and is lecturer at the Technical University of Ilmenau on the topic of retinal vessel analysis.
Peter M. Nilsson
Peter M. Nilsson is a Senior Professor of Clinical Cardiovascular Research and was previously the head of a research group in epidemiology and, for the past 25 years, former head of the Department for History of Medicine, Lund University, Sweden. He has been the acting Director for the Strategic Research Area (SRA) Epidemiolgy for Health (EpiHealth) between 2010 and 2019, linking many experts in epidemiology at the Lund and Uppsala universities in Sweden. He has expertise in diabetes, hypertension, insulin resistance, microbiota, epidemiology, and vascular dysfunction. He co-authored >700 scientific articles. In addition, he is a part-time senior consultant at a Clinical Research Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
Martin Magnusson
Martin Magnusson is a professor and senior consultant in cardiology. Magnusson is PI of the Heart and Brain Failure Investigation study group. Magnusson is a clinically active researcher with special interest in heart failure research, cardiovascular complications to diabetes and predictors of cardiovascular and metabolic disease, e.g., genetic variants, (common and rare), metabolomics, proteomics and targeted biomarkers. He co-authored >92 scientific articles.
Amra Jujic
Amra Jujic is a postdoctoral fellow with her research focusing mainly on heart failure and cardiometabolic disease, with special interest in neuroendocrinology biomarkers.
Daniel W. Mak
Daniel W. Mak completed his PhD in 2019 in Health Sciences at the University of Witwatersrand, South Africa, which focused on hepatitis B virus (HBV), inflammation, hepatocelluar carcinoma and epidemiology in the sub-Saharan African setting. In 2021, he worked as a Postdoctoral Fellow at the University of Hong Kong wherein his research involved understanding induced pluripotent stem cell reprogramming using proteomics and bioinformatic tools.
Faans Steyn
Faans Steyn was a statistical consultant at the Statistical Consultation Services of the North-West University from 1974 to 2008. After retirement, he was appointed by the university in a part-time capacity for another 10 years. During that time, he was involved in epidemiological research and the validation process of the chronic stress and stroke risk phenotype. In his role as statistician, he has co-authored several publications in the field of stress research till date.
Nico T. Malan
Nico T. Malan was Director of the School for Physiology, Nutrition and Consumer Sciences (1991–2010) and in this time he was also Vice-Dean Faculty Health Sciences for 3 years at the North-West University, Potchefstroom South Africa. He became interested in the effect of stress on the health of especially African people in South Africa in 1988. In this regard, he was involved in several studies where the effect of urbanization on African people was studied. This evolved in the study of stress on the retinal and cardiac microvasculature and the role of stress hormones (catecholamines and cortisol) as well as sex hormones (testosterone and estradiol). He has >160 scientific publications.