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Articles   |    
Microvascular Abnormality in Schizophrenia as Shown by Retinal Imaging
Madeline H. Meier, Ph.D.; Idan Shalev, Ph.D.; Terrie E. Moffitt, Ph.D.; Shitij Kapur, M.D., Ph.D.; Richard S.E. Keefe, Ph.D.; Tien Y. Wong, M.D., Ph.D.; Daniel W. Belsky, Ph.D.; HonaLee Harrington, B.S.; Sean Hogan, M.S.W.; Renate Houts, Ph.D.; Avshalom Caspi, Ph.D.; Richie Poulton, Ph.D.
Am J Psychiatry 2013;170:1451-1459. doi:10.1176/appi.ajp.2013.13020234
View Author and Article Information

Drs. Meier and Shalev contributed equally to this study.

Dr. Kapur has received grant support from AstraZeneca, Bristol-Myers Squibb, and GlaxoSmithKline and has served as a consultant, scientific adviser, or speaker for AstraZeneca, Bioline, Bristol-Myers Squibb, Eli Lilly, Janssen (Johnson & Johnson), Lundbeck, NeuroSearch, Otsuka, Pfizer, Roche, Servier, Solvay, and Wyeth. Dr. Keefe has received investigator-initiated research support from the Department of Veterans Affairs, Feinstein Institute for Medical Research, GlaxoSmithKline, NIMH, Novartis, Psychogenics, Research Foundation for Mental Hygiene, and the Singapore National Medical Research Council and has served as a speaker, consultant, or advisory board member for Abbott, Akebia, Amgen, Astellas, Asubio, BiolineRx, Biomarin, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, EnVivo, Helicon, Lundbeck, Merck, Mitsubishi, Novartis, Otsuka, Pfizer, Roche, Shire, Sunovion, Takeda, and Targacept; he also receives royalties from the BACS testing battery and the MATRICS Battery (BACS Symbol Coding) and is a shareholder in NeuroCog Trials. The other authors report no financial relationships with commercial interests.

Supported by grant AG032282 from the National Institute on Aging and grant MR/K00381X from the U.K. Medical Research Council. The Dunedin Multidisciplinary Health and Development Research Unit is supported by the New Zealand Health Research Council. Dr. Meier was supported by grant P30 DA023026 from the National Institute on Drug Abuse. Dr. Shalev was supported by grant HD061298 from the National Institute of Child Health and Human Development and the Jacobs Foundation. Dr. Belsky was supported by grant T32AG000029 from the National Institute on Aging.

From the Department of Psychology and Neuroscience; the Department of Psychiatry and Behavioral Sciences; the Institute for Genome Sciences and Policy; and the Duke Transdisciplinary Prevention Research Center, Center for Child and Family Policy, Duke University, Durham, N.C.; the Social, Genetic, and Developmental Psychiatry Centre and the Department of Psychosis Studies, Institute of Psychiatry, King’s College London; the Department of Ophthalmology and the Singapore Eye Research Institute, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore; the Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; the Center for Aging and the Study of Human Development, Duke University Medical Center, Durham; and the Dunedin Multidisciplinary Health and Development Research Unit, Department of Preventive and Social Medicine, School of Medicine, University of Otago, Dunedin, New Zealand.

Address correspondence to Dr. Moffitt (terrie.moffitt@duke.edu).

Copyright © 2013 by the American Psychiatric Association

Received February 19, 2013; Revised May 15, 2013; Accepted June 03, 2013.

Abstract

Objective  Retinal and cerebral microvessels are structurally and functionally homologous, but unlike cerebral microvessels, retinal microvessels can be noninvasively measured in vivo by retinal imaging. The authors tested the hypothesis that individuals with schizophrenia exhibit microvascular abnormality and evaluated the utility of retinal imaging as a tool for schizophrenia research.

Method  Participants were members of the Dunedin Study, a population-representative cohort followed from birth with 95% retention. Study members underwent retinal imaging at age 38. The authors assessed retinal arteriolar and venular caliber for all members of the cohort, including individuals who developed schizophrenia.

Results  Study members who developed schizophrenia were distinguished by wider retinal venules, suggesting microvascular abnormality reflective of insufficient brain oxygen supply. Analyses that controlled for confounding health conditions suggested that wider retinal venules are not simply an artifact of co-occurring health problems in schizophrenia patients. Wider venules were also associated with a dimensional measure of adult psychosis symptoms and with psychosis symptoms reported in childhood.

Conclusions  The findings provide initial support for the hypothesis that individuals with schizophrenia show microvascular abnormality. Moreover, the results suggest that the same vascular mechanisms underlie subthreshold symptoms and clinical disorder and that these associations may begin early in life. These findings highlight the promise of retinal imaging as a tool for understanding the pathogenesis of schizophrenia.

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FIGURE 1. Retinal Digital Photographa

a Measurements were made for the six largest arterioles (red) and venules (blue) passing through the region located 0.50–2.00 disk diameters from the optic disk margin.

FIGURE 2. Distribution of Retinal Venular Caliber for the Schizophrenia and Comparison Groupsa

a Scores were adjusted for arteriolar caliber and sex and were standardized (mean=0.00, SD=1.00) on the population-representative cohort. The black vertical line represents the mean for the healthy group. Both parametric and nonparametric statistical analyses showed that individuals diagnosed with schizophrenia had significantly wider venules, a finding that does not depend on outliers.

FIGURE 3. Standardized Mean Retinal Venular Caliber at age 38 as a Function of Childhood Psychosis Symptomsa

a Venular caliber values were adjusted for arteriolar caliber and sex and were standardized on the population-representative cohort. As previously described (13), children with scores of 0, 1, and ≥2 were grouped as having no symptoms (N=673; 50.2% were male), weak symptoms (N=103; 66.0% male), or strong symptoms (N=13; 61.5% male), respectively. At minimum, study members could enter the strong symptom group by obtaining a score of 1 (yes, likely) for two symptoms or by obtaining a score of 2 (yes, definitely) for one symptom. Children who exhibited strong psychosis symptoms had the widest venular calibers as adults. Error bars indicate standard error.

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TABLE 1.Standardized Mean Retinal Vessel Caliber for the Schizophrenia and Comparison Groupsa
Table Footer Note

a Mean values for each vessel were adjusted for the other vessel and sex and were standardized on the population-representative cohort (mean=0.00, SD=1.00). Thus, means reflect effect sizes for how different each group is from the cohort norm. Differences between pairs of groups can also be interpreted as effect sizes. Effect sizes of 0.20, 0.50, and 0.80 reflect small, medium, and large effects, respectively.

Table Footer Note

b Significantly different from the healthy group.

Table Footer Note

c Significantly different from the schizophrenia group.

+

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1.
Why can blood vessels in the retina be used to gauge the condition of blood vessels inside the brain?
2.
Research participants with schizophrenia had wider retinal venules than groups with which conditions?
3.
Wide retinal venules are hypothesized to indicate problems with which functions?
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