(Stroke. 2002;33:1487.)
© 2002 American Heart Association, Inc.
Original Contributions |
From the Department of Ophthalmology, University of Wisconsin, Madison (T.Y.W., R.K., B.E.K.K., L.D.H.); Singapore National Eye Center and Department of Ophthalmology, National University of Singapore, Singapore (T.Y.W.); Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Md (F.J.N., M.S.); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md (A.R.S.); Division of Epidemiology, University of Minnesota, Minneapolis (L.L.B.); Department of Biostatistics, University of North Carolina, Chapel Hill (D.J.C.); and Department of Medicine, University of Mississippi Medical Center, Jackson (T.H.M.).
Correspondence to Tien Yin Wong, MD, MPH, Department of Ophthalmology, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore. E-mail ophwty{at}nus.edu.sg
| Abstract |
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Methods The Atherosclerosis Risk in Communities Study is a population-based study with examinations every 3 years from 1987 through 1998. At visit 3, when participants were 51 to 70 years of age, retinal photographs were obtained and evaluated for retinal microvascular abnormalities according to standardized protocols. Cognitive function was assessed with standardized tests (Delayed Word Recall Test, Digit Symbol Subtest, and Word Fluency Test) at visits 2 and 4 and averaged for analysis. Persons with stroke or taking central nervous systemrelevant medications were excluded, leaving 8734 with data for this study.
Results After education, diabetes mellitus, blood pressure, carotid intima-media thickness, and other risk factors were controlled for, retinopathy was associated with lower cognitive test scores. The adjusted odds ratios for persons with Delayed Word Recall scores 2 SD or lower than the mean were 2.60 [95% confidence interval (CI), 1.30 to 2.91] for any retinopathy, 3.00 (95% CI, 1.81 to 4.98) for microaneurysms, 3.39 (95% CI, 1.99 to 5.78) for retinal hemorrhage, and 3.07 (95% CI, 1.53 to 6.17) for soft exudates. Results were similar for the other 2 cognitive tests and in people with and without diabetes and hypertension.
Conclusions Retinopathy is independently associated with poorer cognitive function in middle-aged persons without stroke, suggesting that cerebral microvascular disease may contribute to the development of cognitive impairment.
Key Words: cognitive disorders dementia, vascular hypertension retina retinal diseases
| Introduction |
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Nevertheless, few clinical data are available to support an association between microvascular disease and cognitive impairment, particularly in the general population. In part, the reason is that the cerebral microcirculation is difficult to evaluate outside highly specialized settings.19,20 The retinal arterioles provide a unique opportunity to study the consequences of cerebral microvascular disease because they can be viewed noninvasively and because their anatomy, physiology, and embryology are similar to those of cerebral arterioles.21 Retinal microvascular abnormalities related to aging, hypertension, and other processes have therefore been suggested to reflect similar pathology in the cerebral microcirculation.22
In the Atherosclerosis Risk in Communities (ARIC) study, retinal photographs were obtained of participants at the third visit and graded for retinal microvascular characteristics according to standardized methods.23 We have previously reported that retinal microvascular abnormalities were related to concurrently measured blood pressure and were independently related to past blood pressure24 and various markers of inflammation and endothelial dysfunction.25 We have also shown that retinal abnormalities predict stroke independently of traditional risk factors.26
The purpose of the present study is to examine the association between retinal microvascular abnormalities and cognitive impairment in middle-aged persons free of stroke in the ARIC study.
| Methods |
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Retinal photographs of each participant were taken at visit 3.23 Of the 12 887 who returned for visit 3, we excluded 38 whose race was neither black nor white, 42 black residents in Minneapolis and Maryland, and 174 who did not participate at visit 2. We then excluded 2919 who were using central nervous systemrelevant medications (ie, antipsychotics, antidepressants, anxiolytics, narcotic analgesics, anticonvulsants, and antineoplastic agents) and 265 with a history of stroke up to visit 4, leaving 9623 eligible for these analyses. Of these, 9 had missing blood pressure data, 162 had no retinal photographs, and 544 had ungradable photographs, leaving 8734 who provided data for this study. Characteristics of participants with and without gradable retinal photographs have been previously reported.25 Persons with gradable photographs were younger and more likely to be white but did not differ by sex or smoking status.
Retinal Grading and Definitions
The retinal photography procedure has previously been described in detail.23 Briefly, photographs of the retina were taken of 1 randomly selected eye after 5 minutes of dark adaptation. Trained and certified graders, masked to participant characteristics, evaluated the photographic slides for microvascular abnormalities using standardized protocols. Any retinopathy was defined as present if any of the following lesions were detected: microaneurysms, retinal hemorrhages (blot or flame shaped), soft exudates, hard exudates, macular edema, intraretinal microvascular abnormalities, venous beading, new vessels at the disc or elsewhere, vitreous hemorrhage, disc swelling, or laser photocoagulation scars.23 Similarly, arteriovenous nicking and focal arteriolar narrowing were defined as present if graded definite or probable. Generalized arteriolar narrowing was quantified via a computer-assisted technique. The photographs were digitized by a high-resolution scanner, and the diameters of individual arterioles and venules coursing through a specified zone surrounding the optic disc were measured and summarized as the arteriole-to-venule ratio (AVR). A smaller AVR represents narrower arterioles (because venular diameters vary little),23 and generalized arteriolar narrowing was defined as the lowest 20th percentile of the sample AVR distribution.26 As previously reported, intragrader and intergrader
statistics ranged from 0.61 to 1.00, respectively, for retinopathy, arteriovenous nicking, and focal arteriolar narrowing.23 For AVR, intragrader and intergrader reliability coefficients were 0.84 and 0.79, respectively.
Cognitive Function Tests
Assessment of cognitive function in the ARIC study is described in detail elsewhere.10,13 All participants at visits 2 and 4 had the following 3 neuropsychological tests: the Delayed Word Recall Test,28 the Digit Symbol Subtest of the Wechsler Adult Intelligence ScaleRevised,29 and the Word Fluency Test of the Multilingual Aphasia Examination.30 Trained interviewers administered these tests in a standardized order during 1 session in a quiet room.
The Delayed Word Recall Test is an evaluation of verbal learning and recent memory that requires the person to recall 10 common nouns after a 5-minute interval during which another psychometric test is given.28 Test scores ranged from 0 to 10 words recalled. Test-retest reliability coefficient over 6 months has been reported to be 0.75 in normal elderly individuals.28
The Digit Symbol Subtest is a paper-and-pencil task requiring timed translation of numbers19 to symbols with a key. The test measures psychomotor performance and is relatively unaffected by intellectual ability, memory, or learning.29 It appears to be a sensitive indicator of brain damage, but it is not useful in localizing a lesion.31 The test is scored as the number of numbers translated to symbols correctly within 90 seconds, up to a possible maximum of 93. Test-retest reliability coefficient over 2 to 5 weeks has been reported to be 0.82 in middle-aged persons.29
The Word Fluency Test requires the participant to generate as many words as possible beginning with the letters F, A, and S in 60 seconds for each letter. The test is particularly sensitive to damage in the frontal lobes of the brain.30 The score is the total number of words generated. Test-retest reliability coefficient based on an alternate test form has been reported to be 0.82.30
Definition of Other Variables
Participants underwent standardized cardiovascular assessment at each visit.32 Blood pressure was taken with a random-zero sphygmomanometer, and the mean of the last 2 measurements was used. Mean arterial blood pressure was computed as two thirds of the diastolic value plus one third of the systolic value, and the average of this over the first 3 exams (ie, 6-year mean arterial blood pressure) was included as a covariate in the assessment of the independence of retinal abnormalities with cognitive impairment.26 Education, occupation, diabetes and hypertension history, cigarette smoking, and alcohol consumption were ascertained from examiner-administered questionnaire. Diabetes mellitus was defined as fasting glucose
7.0 mmol/L, nonfasting glucose
11.1 mmol/L, or a self-reported history of physician-diagnosed diabetes or treatment for diabetes. Hypertension was defined as systolic blood pressure
140 mm Hg, diastolic blood pressure
90 mm Hg, or use of antihypertensive medication during the previous 2 weeks. Average internal carotid intima-media wall thickness (IMT) was obtained from standardized B-mode ultrasonograms.32 Blood collection and processing for total plasma cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides are described elsewhere.32 All covariates were based on visit 3 data, except for education and occupation (visit 1), carotid artery IMT (visit 2), and mean arterial blood pressure (average of visits 1 through 3).
Statistical Analysis
Cognitive function scores in the ARIC population were distributed approximately normally and were treated as continuous variables in the analysis.10,13 We evaluated associations of retinal lesions at visit 3 to cognitive test scores that were averaged over visits 2 and 4 among participants who attended all 3 examinations (n=7526). We additionally evaluated retinal associations to cognitive test scores of visits 2 (n=8694) and 4 (n=7552) separately (results were similar and not presented).
We used analysis of covariance to compare the mean cognitive test scores in persons with and without a specific retinal lesion, adjusting for age, sex, race, field center, education (attended grade school or less, attended but did not graduate from high school, graduated from high school, attended vocational school, attended college, attended graduate school), and occupation (professional or manager, other). In multivariate models, we further adjusted for diabetes (yes/no), fasting glucose (mmol/L), hypertension (yes/no), 6-year mean arterial blood pressure (mm Hg), carotid artery IMT (mm), fasting total cholesterol, HDL cholesterol and triglycerides (mmol/L), cigarette smoking (ever/never), and alcohol consumption (ever/never).
To evaluate the retinal associations with extremes in cognitive scores,33 we defined cognitive impairment as scores 2 SD or lower than the mean scores with the following cutoffs: Delayed Word Recall Test,
4; Digit Symbol Subtest,
20; and Word Fluency Test,
11. For each test, we used logistic regression models to determine the odds of cognitive impairment associated with specific retinal lesions, adjusting for potential confounders.
| Results |
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The means (SD) of the average cognitive scores of visits 2 and 4 were as follows: 6.48 (1.3) for Delayed Word Recall, 45.7 (12.8) for Digit Symbol Subtest, and 34.1 (11.6) for Word Fluency Test. After adjustment for age, sex, race, field center, education, and occupation, mean scores of all 3 tests were significantly lower in persons with any retinopathy, microaneurysm, retinal hemorrhage, and soft exudates compared with persons without these lesions (data not shown). Adjustment for diabetes, hypertension, carotid IMT, and other vascular risk factors did not substantially alter these relations (Table 2).
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Results of logistic regression models for cognitive impairment are shown in Table 3. After adjustment, persons with any retinopathy, microaneurysms, retinal hemorrhage, and soft exudates were to 1.4 to 4.1 times more likely to have cognitive impairment than persons without these lesions.
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We repeated analyses in persons with and without hypertension and diabetes separately because these conditions are known to influence retinopathy and cognitive function. The overall pattern of associations was similar (Results based on Delayed Word Recall scores are presented in Table 4). Formal tests of interaction for hypertension and diabetes status in the whole sample by inclusion of cross-product terms (eg, any retinopathy times hypertension) in the logistic regression models did not reveal significant interaction (P>0.20 for all terms).
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Results were generally similar in analyses repeated separately for demographic subgroups stratified by age (51 to 60 years, 61 to 70 years), sex, and race (data not shown). Finally, we attempted to analyze the retinal associations with the 6-year change in cognitive tests scores from visits 2 to 4 (ie, difference in scores between visits 2 and 4). However, the change in scores was minimal in this middle-aged population (eg, change in score for the Delayed Word Recall was <10% of the SD of the mean score).
| Discussion |
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Our study provides further insights into the pathogenesis of cognitive impairment. Although cerebral microvascular disease has been hypothesized to contribute to cognitive impairment,46 data to support such a hypothesis are sparse. Some histopathological studies show Alzheimers disease to be associated with numerous structural and physiological alterations of the cerebral microvasculature, including cerebral arteriolar narrowing,14 arteriolar tortuosity,15 capillary microaneurysms,17 endothelial cell dysfunction,14 and breakdown of the blood-brain barrier.16 One theory is that these anatomic alterations lead to abnormal microvascular flow patterns, impairment in the delivery of nutrients to susceptible neurons, reactive astrocytosis, and finally formation of plaques and neurofibrillary tangles characteristic of severe dementia.6 However, because diseases of the cerebral microcirculation are difficult to assess in vivo, the retinal microvasculature provides a useful noninvasive approach to study the consequences of cerebral microvascular disease. Retinal microvascular abnormalities related to aging and hypertension have been reported to correlate closely with pathological changes in the cerebral microcirculation among stroke decedents34 and have been found in epidemiological studies to be associated with clinical stroke,26,35,36 lacunar infarct,37 and cerebral white-matter lesions.38 Thus, our study supports the hypothesis that cerebral microvascular disease may play an important role in the development of cognitive impairment.
Additionally, these findings offer clues to the specific pathophysiological processes that occur in the cerebral microcirculation of persons with cognitive impairment. The retinal lesions that were related most consistently to lower cognitive scores (eg, microaneurysm, retinal hemorrhages) are indicators of more severe retinal microvascular disease and are usually seen when there is a breakdown in the blood-retinal barrier.21,22 In contrast, other retinal characteristics such as arteriovenous nicking and arteriolar narrowing, which reflect milder microvascular changes,21,22 appear to be related weakly to cognitive impairment. We have also previously shown that incident stroke was more strongly related to retinopathy (multivariable-adjusted relative risk, 2.6) than arteriovenous nicking (multivariable-adjusted relative risk, 1.6) and arteriolar narrowing (multivariable-adjusted relative risk, 1.2).26 Thus, the association with retinopathy but not with arteriovenous nicking and arteriolar narrowing suggests that disruption of the blood-brain barrier of the cerebral microcirculation may be an important pathological feature in the development of stroke and cognitive impairment.16
From a clinical perspective, these data provide additional evidence that cognitive impairment may have a vascular component and may therefore be amenable to treatment and preventive strategies targeted at vascular diseases.39 It is less clear that retinal lesions provide useful independent information regarding risk of cognitive impairment and dementia. Retinopathy is infrequent in the general population, and the retinal assessment in the ARIC study was performed with standardized photographic grading. In addition, differences in cognitive function scores between persons with and without retinopathy were small although statistically significant. Nevertheless, modest deficits detected in midlife may reflect risk of future dementia.39
Limitations of this study should be mentioned. First, because retinal and cognitive assessments were at different study visits, we could compare only retinal microvascular data collected at visit 3 with the average of cognitive tests scores 3 years before (visit 2) and after (visit 4) the retinal examination. This makes it difficult to distinguish clearly cause and effect, although it seems unlikely that cognitive function affects the development of retinal microvascular lesions. Second, selection bias may have obscured some relevant associations and enhanced others. For example, if persons with retinal abnormalities with cognitive impairment were more likely excluded because of ungradable photographs (or other reasons), the observed associations would be falsely attenuated. Finally, visual acuity data were not available, and biases could result if those who could not optimally perform the cognitive tests had visual impairment. However, retinal microvascular changes evaluated in this study are not known to be an important cause of visual impairment.40
In conclusion, we found that in middle-aged persons without stroke, signs of retinal microvascular disease are independently associated with lower cognitive function. The associations suggest that cerebral microvascular disease may be important in the pathogenesis of cognitive impairment. Longitudinal data may clarify the temporal sequence of these associations and the eventual clinical significance of these small, early cognitive function changes.
| Acknowledgments |
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Received December 12, 2001; revision received February 4, 2002; accepted February 20, 2002.
| References |
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