Early detection of psychiatric disorders with retinal imaging would provide a useful noninvasive method for diagnosis and potential treatment early in the disease process. Many studies have looked at, for example, the use of optical coherence tomography (OCT) in Alzheimer’s disease.1

Another area of research interest is bipolar disorder (BD), an impairing mood disorder characterized by episodes of mania or milder hypomania alternating with depression. Mania consists of grandiosity, decreased need for sleep, flight of ideas, distractibility, increase in goal-directed activity and excessive involvement in activities with high potential for consequences, while depression consists of lack of interest in activities, weight loss or change in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, loss of energy, feelings of worthlessness and diminished ability to concentrate.2 More severe episodes, symptoms, comorbidities and functional impairment accompany adolescent-onset BD than the adult form.3,4 Patients with BD also experience a greater prevalence for cardiovascular risk factors (CVRFs) as well as neurocognitive deficits than individuals without BD.5-8

Our Canadian research team of psychiatrists and ophthalmologists have looked at retinal photography as a “window to the mind” to see if we can use it as a non-invasive screening tool for psychiatric disorders like BD. Here’s what we’ve learned.

Retina Photography and CVRFs
Early detection of cardiovascular risk prior to the diagnosis of clinical cardiovascular disease (CVD) is crucial. Current techniques for detecting early atherosclerosis proxies include ultrasound to visualize arterial structure (eg, carotid intima media thickness) or function (eg, flow-mediated dilation).7 However, both techniques are operator-dependent, can be technically challenging and have suboptimal reliability. Additionally, they focus on macrovessels, whereas microvessels may provide a more sensitive assay of early risk of CVD.9 Given the excessive
 
Narrow retinal arterioles (solid arrow) and wider retinal venules (dashed arrow) are indicators of cardiovascular risk factors such as diabetes, high blood pressure and dyslipidemia.
burden and prematurity of cardiovascular risk in BD, this population has a need for practical, reliable, and cost-effective proxies for measuring atherosclerosis, particularly in adolescents.

Retinal photography provides a noninvasive, inexpensive and reliable method of directly visualizing the retinal microvasculature, which is also a proxy for cerebral microvasculature.10-12

Retinal microvessels are arguably the best proxy measures of thcerebrovasculature. First, they can be accurately measured noninvasively. Second, they have several anatomic, embryologic, physiologic and autoregulatory properties similar to cerebral microvasculature.10,12,13 Third, pathological changes in retinal microcirculation have shown an association with cerebrovascular disease.11,14

Current literature indicates that compromised retinal vascular caliber—narrower central retinal arteriolar caliber (CRAE) and wider central retinal venular caliber (CRVE)—is indicative of various CVRFs, including diabetes, body mass index, obesity, high blood pressure and dyslipidemia.15-18 Furthermore, investigators have determined that retinal vascular caliber predicts CVD mortality.19 These associations have also been determined in adolescent populations, where poorer retinal vascular caliber is associated with diabetes, obesity and elevated fasting glucose, body mass index and blood pressure.20-22

Cognitive, Psychiatric Disorders
Retinal vascular caliber is also associated with neurocognitive performance among adults. Wider retinal venular caliber is associated with lower IQ and decreased performance on cognitive domains, including verbal comprehension, working memory, processing speed, executive function and motor skills performance.13 Furthermore, poorer retinal vascular structure has been associated with increased risk for dementia.23 Studies have also reported that symptoms and diagnosis of depression, as well as schizophrenia, are associated with narrower retinal arteriolar caliber and wider retinal venular caliber.24-27
Despite these promising findings, important gaps exist in the literature on retinal vascular photography and how it relates to cardiovascular and neurocognitive aspects. No prior retinal vascular photography studies have focused on BD in any age group, or on neurocognition specifically in adolescents.  

Retinal Photography For Integrative Research
The multidisciplinary Canadian study team focused on cardiovascular risk in BD includes ophthalmology, psychiatry, neurology and medical imaging. We are using retinal photography as a novel tool to reliably measure cerebral microvessels.

The goal of this project was to generate through retinal photography novel discoveries about early stages of CVD and neurocognitive impairment in a population highly susceptible to both. This study aimed to examine the association of both CVRFs and neurocognition among adolescents with BD as well as among adolescents who are at high risk for developing BD (that is, they have a parent or a sibling with BD).

We hypothesized that narrower CRAE and wider CRVE would be associated with greater metabolic syndrome components (increased triglycerides, systolic and diastolic blood pressure, glucose and waist circumference, and decreased high-density lipoprotein cholesterol), poorer peripheral endothelial function and poorer frontal-executive neurocognitive task performance.

Thus far the
 
study has enrolled 30 adolescents with BD and 32 healthy controls. A certified ophthalmic assistant performs mydriatic retinal photography to optimize image capture. The study uses anthropometric measures as well as a fasting lipid panel to obtain CVRFs, and bases neurocognitive measures on performance on computer-based tasks using the Cambridge Neuropsychological Tests Automated Battery (CANTAB) software.

Preliminary findings, presented recently at the Society for Biological Psychiatry and Canadian College of Neuropsychopharmacology conferences suggest that poorer retinal vascular caliber is associated with both increased CVRFs and neurocognitive deficits among adolescents with BD, but not in healthy controls. Specifically, higher diastolic blood pressure is associated with lower (worse) arterio-venular ratio (AVR) in the BD group. Similarly, higher (better) endothelial function is associated with higher (better) AVR in the BD group.

With regards to neurocognition, higher (better) AVR is associated with better performance on a task of attention and executive function among BD adolescents. None of these are significant in the health controls.
The theme of early identification and treatment is important in BD, as it is in other medical conditions. Because BD is perhaps the most familial psychiatric condition, examining relatives of people with BD may offer insights that can help parse factors that give rise to or precede BD from those that emerge contemporaneously with symptoms. Adolescent offspring of parents with BD are at an increased risk of developing BD themselves27-29 and can thus provide insights into underlying cardiovascular risk, independent of the effects of BD.28,30-32

If retinal vascular measures are meaningfully associated with BD, CVRFs and neurocognition, one can foresee a future in which retinal vascular photography has practical applications in the diagnosis, monitoring and early treatment of BD. If we succeed in our goal of demonstrating the relevance of retinal vascular measures to early-onset BD, this will provide the rationale for further development of this pragmatic method of early identification and monitoring of BD. In particular, we intend to integrate vascular-related neuroimaging phenotypes and longitudinal repeated measures. This study will provide an excellent platform for future, larger-scale, longitudinal studies. Overall, this study comprises an important step toward better understanding adolescent BD and its relation to increased cardiovascular risk and neurocognitive deficits.  RS

Dr. Mandelcorn is an assistant professor of ophthalmology at the University of Toronto, where Ms. Naiberg is also a PhD candidate, Dr. Kertes a vitreoretinal surgeon and Dr. Goldstein an associate professor of psychiatry and pharmacology.

DISCLOSURES: The authors have no relevant disclosures.


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