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Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study
Alzheimer’s & Dementia - (2018) 1-10
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Research Article
Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study Jennifer A. Deala,*, A. Richey Sharretta, Marilyn Albertb, Karen Bandeen-Rochec, Sheila Burgardd, Sonia Davis Thomase, Rebecca F. Gottesmana,b, David Knopmanf, Thomas Mosleyg, Barbara Kleinh, Ronald Kleinh a
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA b Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA c Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA d Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA e RTI International, Research Triangle Park, NC, USA f Department of Neurology, Mayo Clinic, Rochester, MN, USA g Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA h Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Abstract
Introduction: The easily-imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia. Methods: In a population-based study of 12,482 adults aged 50-73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993-1995) with incident all-cause dementia (1993-1995 to 2011-2013) and with etiologic subtype of dementia/ mild cognitive impairment (2011-13). Results: A total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/ severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36–2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09–1.45) were associated with all-cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular-related, but not Alzheimer’s-related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24–4.23). Discussion: Exploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia. Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association.
Keywords:
Cohort studies; Dementia; Diabetes; Microvasculature; Retinal; Risk factors in epidemiology
1. Introduction Vascular disease is a recognized, potentially modifiable contributor to dementia in older adults [1]. Retinal fundus photography noninvasively images small vessel changes in the eye which may resemble similar changes in the brain
*Corresponding author. Tel.: 1410-955-0491; Fax: ---. E-mail address: [email protected]
[2,3]. Retinal signs measured through fundus photography may therefore be a surrogate measure of microvasculature damage in the brain and so may be related to increased dementia risk. Retinal signs are risk factors for incident clinical stroke [4,5] and for early and largely silent cerebral changes [4,6], including ventricular enlargement [7], silent lacunesize cerebral infarcts, incident white matter lesions, and white matter hyperintensity progression [8]. However, population-based epidemiologic studies of retinal signs
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and dementia are few in number with limited prospective follow-up [9]. A recent systematic review underscored the need for future studies to describe the relationship between retinal signs and dementia subtypes [9]. We addressed this research gap using data from the Atherosclerosis Risk in Communities (ARIC) Study, a large, population-based prospective cohort, to test the hypothesis that retinal signs in midlife (1993-1995) are related to increased risk of incident all-cause dementia over 20 years (1993-1995 to 2011-2013) and to etiologic subtype of a combined outcome of dementia or mild cognitive impairment (MCI) in 2011-13.
2. Methods 2.1. Study population ARIC is a population-based prospective study of 15,792 men and women aged 45-64 years at baseline (1987-1989) from four US communities: (1) Washington County, Maryland; (2) Forsyth County, North Carolina; (3) Jackson, Mississippi; and (4) Minneapolis, Minnesota (Fig. 1) [10]. Informed consent was obtained from all participants at each visit or from a designated proxy with participant assent if the participant was unable to provide consent (e.g., known dementia diagnosis). Study procedures were approved by the Institutional Review Board for each field center. For this study, participants were excluded if race was other than black or white (N 5 48) or non-white from Minneapolis or Washington County sites (N 5 55). Also excluded were 7 participants who had a dementia diagnosis before retinal photographs were collected (visit 3, 19931995), 2882 who did not attend visit 3, and 241 who did not have an interpretable photograph. Participants were also excluded if data on retinopathy severity (N 5 4), education (N 5 19), or—given its strong relationship with retinopathy—diabetes status (N 5 54) are missing, yielding an analytic sample of 12,482. Excluded participants were older (55 vs. 54 years); more likely to be African American (45% vs. 22%); a current smoker (39% vs. 23%) and former drinker (26% vs. 17%); more likely to have diabetes (19% vs. 10%), hypertension (46% vs. 32%), and coronary heart disease (CHD) (8% vs.
4%); and more likely to die during follow-up (55% vs. 26%) than participants included in the study (Supplemental Table 1). 2.2. Diagnosis of dementia during follow-up Dementia diagnosis in this cohort has been described elsewhere [11,12] and was ascertained for all participants, including those who died during follow-up. For all participants who survived until and attended the fifth clinic visit (2011-2013; Fig. 1), diagnosis was performed using standardized algorithms incorporating longitudinal cognitive data and a complete neuropsychological battery that was administered at visit 5, with all algorithmic diagnoses confirmed by expert panel review. Dementia diagnoses for participants who did not attend visit 5 were based on a Modified Telephone Interview for Cognitive Status (TICS) interview with the participant, on modified Clinical Dementia Rating (CDR) interviews with informants confirming a hospital International Classification of Diseases, Ninth Revision (ICD-9) discharge or death certificate dementia code, or on hospital or death certificate dementia codes alone [12,13]. Active surveillance for dementia continued through the date of last participant contact up to September 1, 2013. For diagnosis ascertained by codes, the date of dementia onset was estimated to be 6 months before the hospitalization. 2.3. MCI diagnosis and etiologic subtyping of dementia and MCI at visit 5 MCI and etiologic subtype of dementia or MCI was adjudicated only for the subset of participants who attended the final clinic visit in 2011-13; the adjudication process has been previously described [11]. MCI diagnosis was based on full neuropsychological assessment at visit 5, CDR, Functional Activities Questionnaire, Neuropsychiatric Inventory, and brain magnetic resonance imaging (MRI) [11]. Alzheimer’s disease (AD) etiology was diagnosed based on the nonabrupt onset of cognitive syndrome, including memory impairment and absence of a cerebrovascular disease (CVD), Lewy body, or other (e.g., medication or alcohol induced) diagnoses [11,14,15]. CVD etiology was diagnosed based on a history of stroke with or without
• Renal Photography N=12,645
Visit 1
Visit 2
Visit 3
Visit 4
1987-89
1990-92
1993-95
1996-98
• Cognion N=15,782 N=14,214
• Cognion N=12,645
Visit 5 2011-13
Neurocognive Study (ARIC-NCS) • Full cognive baery (N=6,411) • Brain MRI (N=1,968) • Demena/MCI eology (N=2,168)
Demena Surveillance
Fig. 1. Atherosclerosis Risk in Communities (ARIC) Study Design. Abbreviations: MRI, magnetic resonance imaging; MCI, mild cognitive impairment.
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reported subsequent abrupt onset of cognitive impairment using the validated National Institute of Health Stroke Scale, evidence of stroke on neurologic examination, and small vessel disease evidenced by MRI (e.g., lacunes and white matter hyperintensities volume) [11,16]. In this analysis, AD-related dementia or MCI was defined as any case assigned an AD etiology without evidence of CVD-related etiology. CVD-related dementia or MCI was defined as any CVD etiology, with or without AD-related etiology. 2.4. Retinal exposures Photographs (visit 3) were obtained in a single, randomly selected eye for each participant by trained technicians using nonmydriatic fundus cameras. All photographs were assessed at a central reading center by trained, certified graders masked to participant characteristics, with moderate-togood intergrader reliability [17]. The presence of retinal lesions was assessed using the modified Airlie House classification, as used in the Early Treatment Diabetic Retinopathy Study [17], and retinopathy severity was classified as follows: (1) none (retinopathy severity level ,14); (2) mild (14-34); (3) moderate (35-46); and (4) severe (47). Given the small number of participants with severe retinopathy (N 5 26), retinopathy was categorized as none, mild, or moderate/severe for analysis. Microaneurysms, retinal hemorrhages (flame- and/or blot-shaped), and soft exudates were considered present if one or more “definite” signs were present. Focal arteriolar narrowing was defined as “definite” based on number and grading of arterioles estimated to be 50 mm in diameter that had a constricted area less than or equal to two-third of the width of proximal and distal vessel segments. Arteriovenous (AV) nicking was defined as “definite” based on number and grading of at least one venous blood column that was tapered on both sides of its crossing underneath an arteriole. Generalized arteriolar narrowing was evaluated using enhanced images and an imageprocessing software program. Arteriolar diameters within a prespecified zone surrounding the optic nerve were quantified as the central retinal arteriolar equivalent (CRAE) using the following formula to adjust for branching [18]. Arterioles qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Wc 5 0:87 W 2a 1 1:01 W 2b 20:22 Wa Wb 210:76 where Wc 5 the caliber of the trunk vessel Wa 5 the caliber of the smaller branch, and Wb 5 the caliber of the larger branch Generalized narrowing was defined as the lowest CRAE quartile [19]. 2.4.1. Other variables Demographic information collected at study baseline (1987-1989) includes birth date (for calculating age at study
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visit), sex, race, and education (,high school, high school or equivalent, or .high school). Other covariates were measured when retinal photographs were collected (visit 3, 1993-1995), including smoking and drinking status, each coded as never, former, or current; body mass index (kg/ m2), calculated using measured weight and height; prehypertension, defined in persons not taking antihypertensive medication as diastolic blood pressure 80-89 mmHg or systolic blood pressure 120-139 mmHg; hypertension, defined as diastolic blood pressure 90 mmHg, systolic blood pressure 140 mmHg, or antihypertensive medication use; and diabetes defined as fasting blood glucose level 126 mg/dL, nonfasting glucose 200 mg/dL, self-reported diabetes (as diagnosed by a physician), or use of diabetes medication. CHD was defined by self-reported history at baseline and adjudicated fatal CHD, myocardial infarction, silent myocardial infarction, coronary artery bypass surgery, or angioplasty through visit 3. Prevalent stroke was defined as self-reported history of stroke diagnosed by a physician at baseline and adjudicated stroke through visit 3. Apolipoprotein (APOE) genotype was categorized as the number of ε4 Q3 alleles (0 vs. 1) [11]. 2.5. Statistical analysis Hazard ratios (HRs) of time to dementia (1993-2013) from date of retinal photography (1993-1995) comparing participants with and without retinal signs were estimated using Cox proportional hazard models. Although our surveillance methods may not identify the date of dementia onset accurately, the Cox models, as implemented, have been shown to yield similar results to a discrete time analysis (time divided into 5-year intervals) that relaxes assumptions about exact diagnosis date [12]. The proportional hazards assumption was verified by assessing correlation between scaled Schoenfeld residuals and transformed survival times, handling ties using the Efron method. Primary analyses were stratified by diabetes status, race, and APOE genotype based on a priori hypotheses, with a formal test for interaction by diabetes, race, sex, and APOE status. Analyses were adjusted for age (linear and quadratic terms), sex, an interaction between race and study site (in nonstratified models), body mass index (BMI), smoking, drinking, hypertensive status (none, prehypertension, hypertension), diabetes (in nonstratified models), CHD, and a history of stroke. In a sensitivity analysis, we adjusted for hemoglobin A1c measured at visit 2 (1990-92); hemoglobin A1c is not available at the time when the retinal photographs were taken. Missing covariate and exposure data were imputed with 20 sets of multiple imputation using chained equations (MICE) [20]. The number of imputed values for each variable is as follows: (1) AV nicking, N 5 1659; (2) focal narrowing, N 5 2169; (3) CRAE, N 5 1598; (4) microaneurysms, N 5 1581; (5) retinal hemorrhages, N 5 949; (6) soft exudates, N 5 636; (7) BMI, N 5 13; (8) drinking status, N 5 8; (9) hypertension, N 5 64; (10) CHD status,
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N 5 251; and (11) stroke status, N 5 26. The imputation model included all covariates in the final model, as well as the APOE ε4 genotype, and systolic and diastolic blood pressures, cognitive function, glucose, and hemoglobin A1c measured at visit 2. To assess for a possible ascertainment bias, we repeated analyses censoring individuals after a hospitalization ICD9 code for comorbidities related to retinal signs, including ischemic heart disease (400-404) or CVD (430-438). Given the strong association of retinal signs with mortality in this cohort and to aid in the interpretation of the estimated cause-specific hazards of the relationship between retinal signs and dementia, we conducted a competingrisks sensitivity analysis using Cox proportional hazards models to compare risk of nondementia death in persons with and without retinal signs, treating dementia before death as a censoring event [21]. Studies on the relationship between retinal signs and dementia subtypes are needed [9]. However, in this cohort, etiologic subtype of dementia and MCI was adjudicated only in the subset of participants who survived until and attended the final clinic visit (visit 5). Therefore, in a secondary, complementary analysis, we used generalized linear regression with a complementary log-log link to model the HR of etiologic subtype of dementia or MCI in the subset of participants who attended visit 5 (2011-2013) with the retinal variables assessed w20 years previously (visit 3, 1993-1995). As the same etiologic classification was conducted for both MCI and dementia and because of the small numbers of events at visit 5, dementia and MCI were modeled as a joint outcome to increase stability of the results. To minimize the likelihood of a finding solely due to chance, analysis was restricted to those retinal signs that were associated with dementia in the primary model. Analyses were conducted in Stata 13 (StataCorp 2013. Stata Statistical Software: Release 13; StataCorp LP, College Station, TX). 3. Results Of 12,482 participants, 11,838 (95%), 379 (3%), and 265 (2%) were classified as having no, mild, or moderate/severe retinopathy, respectively (Table 1). Participants with moderate/severe retinopathy were more likely to be African American, less educated, never drinkers; to have hypertension, CHD and history of stroke, and greater BMI; and to die during follow-up than participants with no or mild retinopathy (Table 1). Eighty-four percent (N 5 222) of participants with moderate/severe retinopathy had diabetes compared with 13% with no retinopathy. Over a mean follow-up of 16 years, 1259 participants (10%) developed incident dementia. Twenty-five percent (N 5 310) of cases were diagnosed using visit 5 data and expert review, 44% (N 5 552) using the TICS or dementia codes confirmed by CDR, and 32% (N 5 397) using hospital or death codes alone. Seventeen percent of participants with
moderate/severe retinopathy developed dementia during the study period, as compared with 13% for mild and 10% for no retinopathy (Table 2). After full adjustment, the HR for incident dementia associated with mild (vs. no) retinopathy was 1.44 (95% confidence interval [CI]: 1.08–1.92) and that associated with moderate/severe (vs. no) retinopathy was 1.86 (95% CI: 1.36–2.55; Table 2). After adjustment for hemoglobin A1c levels, these associations were attenuated to 1.41 (95% CI: 1.05–1.88) and 1.60 (95% CI: 1.14–2.24). CRAE (narrowest quartile vs. widest three quartiles) was also associated with increased dementia risk (HR, 1.23; 95% CI: 1.07–1.41; Table 2). AV nicking and focal narrowing were not associated with dementia risk (Table 2). Available-case models that did not impute missing exposure data yielded nearly identical effect estimates (Supplemental Table 2). Retinopathy components (microaneurysms, retinal hemorrhages, and soft exudates) were independently associated with greater risk of incident dementia, although the association with soft exudates was not statistically significant (Table 2). Estimates of dementia risk associated with each retinal sign were qualitatively greater in men versus women and, with the exception of CRAE, in persons with (vs. without) diabetes (Fig. 2). However, P values for an interaction between sex and retinal signs, as well as between diabetes and retinal signs, were not significant for any retinal exposure. Mild retinopathy and CRAE were significantly associated with dementia risk in men but not in women. For mild retinopathy, the HR was 1.57 (95% CI: 1.03–2.40) in men versus 1.35 (95% CI: 0.90–2.02) in women (p-interaction 5 0.600); for CRAE, the HR was 1.37 (95% CI: 1.11–1.68) in men versus 1.15 (95% CI: 0.95–1.40) in women (p-interaction 5 0.422). Moderate/severe retinopathy was the only retinal sign in which the association was statistically significant in persons with diabetes but was not for persons without diabetes; compared with no retinopathy, moderate/ severe retinopathy was associated with a 2.14 (95% CI: 1.50–3.04) increased hazard of dementia in participants with diabetes and 1.29 (95% CI: 0.57–2.90) in participants without diabetes (p-interaction 5 0.310). We did not find statistical evidence that relationships between retinal signs and dementia differed by race or APOE ε4 allele status. In a sensitivity analysis that censored participants following a hospitalization code for CVD or ischemic heart disease, the HR for incident dementia associated with moderate/severe retinopathy was 3.34 (95% CI: 1.79–6.26), and that associated with CRAE was 1.41 (95% CI: 1.12–1.79). Overall, 23% of participants died before a dementia diagnosis during follow-up. Mortality was more common in participants with retinal signs present: (1) moderate/severe retinopathy, 51% versus 31% (mild) and 22% (none); (2) AV nicking, 30% versus 21%; focal narrowing, 29% versus 20%; and (3) CRAE, 23% versus 21% (Table 3). In a competing risks sensitivity analysis, all retinal signs except
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CRAE were associated with increased risk of death over the 20 years of follow-up. The cause-specific HR for death associated with mild (vs. no) retinopathy was 1.22 (95% CI: 1.01–1.48); moderate/severe (vs. no) retinopathy, 1.81 (95% CI: 1.50–2.17); AV nicking, 1.16 (95% CI: 1.01– 1.34); focal narrowing, 1.25 (95% CI: 1.09–1.44); and CRAE, 1.07 (95% CI: 0.97–1.18) (Table 3). Restricting to participants who attended visit 5 and excluding participants with an unknown etiologic subtype, 294 (5%) participants had dementia and 1091 (19%) had MCI. For a joint outcome of MCI and dementia, N 5 1196 (86%) had any AD-related etiologic diagnosis, of whom N 5 470 (34%) had a pure AD-related etiology and 686 (14%) had an AD-related diagnosis without evidence of CVD. Only 20 participants had a pure CVDrelated etiology and N 5 549 had a primary or secondary
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etiologic CVD diagnosis. In fully adjusted models, moderate/severe retinopathy was associated with increased risk of MCI/dementia with cerebrovascular, but not AD, etiology. The HR comparing moderate/severe with no retinopathy was 1.33 (95% CI: 0.64–2.77) for AD-related dementia or MCI without evidence of CVD and 2.29 (95% CI: 1.24–4.23) for MCI or dementia with any cerebrovascular etiology (Table 4). No associations were found for CRAE and either etiologic subtype. 4. Discussion In this study of 12,482 men and women (aged 50-73 years, 22% African American), two retinal signs—retinopathy severity and CRAE, markers of small vessel integrity and vessel wall integrity and dimensions, respectively—were
Table 1 Baseline (visit 3, 1993-1995) characteristics by retinopathy severity, Atherosclerosis Risk in Communities (ARIC) study (N 5 12,482)
Q6
Retinopathy severity
y
Age (years) Black race Female Education ,High school High school .High school Body mass index (kg/m2)y Smoking status Never Former Current Drinking status Never Former Current Diabetes Hypertension No hypertension Prehypertension Hypertension Stroke Coronary heart disease APOE ε4 genotype 0 ε4 alleles 1 ε4 alleles Follow-up status Died during follow-up Living, did not attend visit 5 Attended visit 5 (2011-13) Follow-up timey Other retinal measures Arteriovenous (AV) nicking Focal arteriolar narrowing CRAE (lowest quartile)
Total (N 5 12,482)
None (N 5 11,838)
Mild (N 5 379)
Moderate/severe (N 5 265)
N (%)
N (%)
N (%)
N (%)
P value*
60.5 (5.7) 2782 (22) 6929 (56)
60.4 (5.7) 2519 (21) 6580 (56)
60.7 (5.7) 134 (35) 200 (53)
61.1 (5.7) 129 (49) 149 (56)
.070 ,.0001 .540
2498 (20) 5229 (42) 4755 (38) 28.5 (5.5)
2302 (19) 4987 (42) 4549 (38) 28.4 (5.4)
97 (26) 150 (40) 132 (35) 29.4 (5.8)
99 (37) 92 (35) 74 (28) 31.4 (6.9)
,.0001
5115 (41) 5158 (41) 2196 (18)
4841 (41) 4897 (41) 2088 (18)
155 (41) 154 (41) 69 (18)
119 (45) 107 (40) 39 (15)
.651
3073 (25) 2851 (23) 6545 (52) 1905 (15)
2873 (24) 2654 (22) 6301 (53) 1581 (13)
108 (29) 102 (27) 166 (44) 102 (27)
92 (35) 95 (36) 78 (29) 222 (84)
,.0001
4289 (35) 3064 (25) 5065 (41) 232 (2) 868 (7)
4167 (35) 2947 (25) 4665 (40) 203 (2) 794 (7)
88 (23) 75 (20) 212 (57) 14 (4) 38 (10)
34 (13) 42 (16) 188 (71) 15 (6) 36 (14)
84,162 (70) 3662 (30)
7991 (70) 3461 (30)
244 (66) 125 (34)
181 (70) 76 (30)
.312
3234 (26) 3224 (26) 6024 (48) 15.6 (4.4)
2936 (25) 3069 (26) 5833 (49) 15.7 (4.3)
136 (36) 107 (28) 136 (36) 14.6 (5.0)
162 (61) 48 (18) 55 (21) 12.2 (5.9)
,.0001
1641 (14) 1688 (15) 2741 (25)
1502 (14) 1538 (14) 2596 (25)
71 (19) 96 (27) 92 (25)
68 (27) 54 (22) 53 (24)
,.0001 ,.0001 .900
Abbreviations: APOE, apolipoprotein E; CRAE, central retinal arteriolar equivalent. *P-values from one-way analysis of variance test or Kruskal-Wallis test (continuous variables) or Pearson’s chi2 test (categorical variables). y Values expressed as mean (SD).
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,.0001
,.0001 ,.0001 ,.0001 ,.0001
,.0001
537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597
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598 599 600 601Q7 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658
Table 2 Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the relationship between retinal signs (visit 3, 1993-1995) and incident all-cause dementia (1993-2013), Atherosclerosis Risk in Communities (ARIC) study Incident dementia HR Ndementia/Ntotal (%) (95% CI) Retinopathy severity None Mild Moderate/severe Retinopathy components Microaneurysms No Yes Retinal hemorrhages No Yes Soft exudates No Yes Arteriovenous nicking No Yes Focal narrowing No Yes CRAE No (top 3 quartiles) Yes (bottom quartile)
P value
1165/11,838 (10) 48/379 (13) 46/265 (17)
Referent – 1.44 (1.08, 1.92) .014 1.86 (1.36, 2.55) ,.0001
986/10,421 (9) 71/480 (15)
Referent – 1.61 (1.25, 2.07) ,.0001
1073/11,151 (10) 65/382 (17)
Referent – 1.81 (1.40, 2.35) ,.0001
1151/11,688 (10) 21/158 (13)
Referent 1.40 (0.89, 2.19)
– .145
958/10,154 (9) 74/669 (11)
Referent 1.11 (0.88, 1.39)
– .389
865/9505 (9) 98/808 (12)
Referent 1.17 (0.94, 1.45)
– .161
749/8143 (9) 298/2741 (11)
Referent 1.23 (1.07, 1.41)
– .004
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRAE, central retinal arteriolar equivalent. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and exposure data.
independently associated with increased risk of all-cause dementia over 20 years. In analyses adjusted for demographic and clinical covariates, we observed a dose-dependent association between retinopathy severity (none, mild, and moderate/severe) and dementia, with the strongest association observed for moderate/severe (vs. none) retinopathy; p-trend ,0.0001. Similar associations were observed for retinopathy components (microaneurysms, retinal hemorrhages, and soft exudates), although the association for soft exudates was not statistically significant, likely due to limited sample size (N 5 158 participants with soft exudates). Among the 25% of participants with the narrowest retinal arterioles as measured by CRAE, the risk of dementia was increased by 23%. The relationship between moderate/severe retinopathy and dementia was stronger for persons with diabetes than for persons without diabetes (HR, 2.14 vs. 1.29). This might suggest that moderate/severe retinopathy is a marker for diabetes severity, rather than a specific marker for microvascular disease in the brain. However, the number of participants in this study who have moderate/severe retinopathy but not diabetes was small (N 5 43), limiting precision
of the estimate in the group without diabetes. In addition, in a sensitivity analysis that adjusted for hemoglobin A1c, a marker of long-term hyperglycemia, moderate/severe retinopathy remained associated with dementia during followup, although the effect estimate was attenuated by 14%; it is a limitation of this study that hemoglobin A1c was not measured concurrently with the retinal photographs but at an average of 3 years before the time when the retinal photographs were taken. Our primary analysis used a dementia diagnosis that incorporated multiple data sources. For the majority of participants, dementia was diagnosed using a standardized algorithm and expert panel review using up to 20 years of longitudinal cognitive data, including a full neuropsychological battery administered at the fifth clinic visit (2011-2013). However, because those who survived and attended visit 5 were a select group (for example, 79% of participants with moderate/severe retinopathy did not attend visit 5; Table 1), we ascertained dementia cases which occurred before the final clinic visit using community-wide hospital and death certificate surveillance. Use of this surveillance data permits our examining early dementias, which, as was reported previously [13], are the cases most strongly associated with classical vascular risk factors. An important concern with using dementia cases ascertained in this manner is that the risk of hospitalization (therefore ascertainment and diagnosis) may be related to the exposure, which could therefore result in overestimation of the association between retinal signs and dementia. However, retinop- Q4 athy- and CRAE-dementia associations were even stronger when participants were censored after hospitalization for ischemic heart disease or CVD (HR, 3.34 and 1.41, respectively) and when cases diagnosed by only hospital or death certificate codes were excluded (OR, 2.53 and 1.26, respectively), suggesting that our findings are not only due to ascertainment bias or misclassification of dementia. In our primary analysis, we estimated the cause-specific HR for dementia before death, comparing participants with and without retinal signs. Inferences from this model type are appropriate and useful for etiologic research questions but should not be interpreted as the effect of retinal signs on the absolute risk of the dementia over time, as the latter inference is dependent on the survival function, both for dementia and for death. To aid in the interpretation of our findings, we conducted a competing risks analysis to estimate the cause-specific hazard of death before dementia. Estimated associations for retinopathy were strong for both dementia and death. Although we found no association between AV nicking and focal narrowing and dementia, both signs were related to death before a dementia diagnosis. In our study, MCI and etiologic diagnosis of both MCI and dementia were adjudicated using the full neuropsychological battery and MRI brain imaging administered only at visit 5. Consistent with the hypothesis that fundus photography may provide insight into small vessel brain disease, we found that moderate/severe (vs. none) retinopathy was
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Retinopathy: Moderate/Severe
A
P-interaction: 0.310
Diabetes
0.760 Black race
0.517
N=10577
0.461
0.508
0.869
No Diabetes
N=9700 0.5 1.0 1.5 2.0 2.5 3.0
C
0.5 1.0 1.5 2.0 2.5 3.0
P-interaction: 0.600
Females
0.759
N=6929
0.750 ≥1 ε4 alleles
0.405
N=3662
0.598
Focal Narrowing CRAE
P-interaction: 0.631
D
0.933
Mild AV Nicking
0.802
White race
N=1905
Retinopathy: Moderate/Severe
0.818
N=2782
Focal Narrowing CRAE
P-interaction: 0.470
0.613
Mild AV Nicking
B
7
0.422
Males N=5553
0.502 0.799
No ε 4 alleles N=8416
0.5 1.0 1.5 2.0 2.5 3.0
0.5 1.0 1.5 2.0 2.5 3.0
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
Fig. 2. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) of the relationship between retinal signs (visit 9, 1993-1995) and incident dementia (1993-2015) by diabetes status, race, sex, and number of APOE ε4 alleles, Atherosclerosis Risk in Communities (ARIC) Study adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This figure includes imputed values for missing exposure and covariate data. (A) Results stratified by diabetes status (N 5 12,482). (B) Results stratified by race (N 5 12,482). (C) Results stratified by sex (N 5 12,482). (D) Results stratified by number of APOE ε4 alleles (N 5 12,078). Abbreviations: AV, arteriovenous; CRAE, central retinal arteriolar equivalent; BMI, body mass index; CHD, coronary heart disease; APOE, apolipoprotein E.
associated with a joint outcome of MCI and dementia for cerebrovascular-related etiologies (primary or secondary), but not for AD-related etiology without evidence of CVD. Although limitations in the study design did not allow for the most appropriate methods to handle censoring for this research question (i.e., measures used to adjudicate etiology were only collected at one point in time), this secondary analysis does address an important research gap—that of the relationship between retinal signs and etiologic subtype of dementia [9]—and, given the strong association with retinal signs and mortality, may be a conservative estimate of the relationship between retinal signs and the cerebrovascular subtype. These findings should be replicated in a study with dementia etiology adjudicated at more than one time point. Only one prospective study (Rotterdam) with similar retinal measures to ARIC has been published on this topic. Unlike our study, no associations were reported. Neither baseline retinopathy (age and sex-adjusted OR: 1.2, 95% CI: 0.9–1.5; N 5 6078) [22] nor CRAE (OR: 1.05, 95% CI: 0.96–1.16; N 5 5553) [23] were associated with dementia risk over a mean follow-up of 11 years. The potential use of fundus photography for differentiating dementia subtypes using large, well-powered study populations was highlighted in a recent systematic review [9]. Our study addresses this research gap with a large sample size in a biracial popula-
tion, retinal signs measured in midlife with up to 20 years of follow-up, and well-characterized dementia and MCI etiologic outcomes. Methodologically, we accounted for potential bias due to missing covariate data with multiple imputation and assessed the robustness of our findings to ascertainment bias in sensitivity analysis. One minor limitation of our study is that retinal photographs were taken in only one (randomly selected) eye; although we do not expect differences between the left and right eyes, having both eyes would potentially allow for more accurate ascertainment of the presence of retinal signs. An additional limitation of this analysis is that retinal photographs were only measured at only one time point. Unmeasured and residual confounding is a threat to inference in any observational epidemiologic study. However, covariates found to be associated in prior analyses of dementia risk in this cohort which may also be related to retinal signs have been included in this analysis and defined similarly to prior investigations [12]. This study documented an association of two midlife retinal signs—retinopathy and generalized arteriolar narrowing (measured as CRAE)—with greater 20-year risk of all-cause dementia in 12,482 men and women from four US communities. This association was observed for both white and black participants, and it did not differ by APOE ε4 genotype. Retinopathy associations were significant
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Table 3 Competing risk analysis of the relationship between retinal signs (visit 3, 1993-1995) and mortality (1993-2013), Atherosclerosis Risk in Communities (ARIC) study
Retinopathy severity None Mild Moderate/severe Retinopathy components Microaneurysms No Yes Retinal hemorrhages No Yes Soft exudates No Yes Arteriovenous nicking No Yes Focal narrowing No Yes CRAE No (top 3 quartiles) Yes (bottom quartile)
Deaths Ndeaths/Ntotal (%)
HR (95% CI)
P value
2560/11,838 (22) 116/379 (31) 136/265 (51)
Referent 1.22 (1.01, 1.48) 1.81 (1.50, 2.17)
– .035 ,.0001
2135/10,421 (20) 198/480 (41)
Referent 1.51 (1.30, 1.76)
– ,.0001
2344/11,151 (21) 184/382 (48)
Referent 1.74 (1.48, 2.04)
– ,.0001
2532/11,688 (22) 80/158 (51)
Referent 1.82 (1.45, 2.29)
– ,.0001
2098/10,154 (21) 199/669 (30)
Referent 1.16 (1.01, 1.34)
– .040
1919/9505 (20) 235/808 (29)
Referent 1.25 (1.09, 1.44)
– .002
1703/8143 (21) 629/2741 (23)
Referent 1.07 (0.97, 1.18)
– .151
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; CRAE, central retinal arteriolar equivalent; HR, hazard ratio. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and exposure data.
only in persons with diabetes, but the converse was true for CRAE—associations were strongest in persons without diabetes. In analyses of midlife retinal signs and etiologic diagnoses of MCI and dementia adjudicated 20 years later, retinopathy was associated with cerebrovascular-related, but not Alzheimer’s-related, impairments in the absence of CVD. Future studies should investigate the mechanism underlying these relationships.
The extent of the microvascular contribution to the development of dementia may be unrecognized because of the inability to visualize the brain microvasculature in vivo [24–28]. However, fundus photography and emerging, more sensitive, imaging techniques in the eye, such as optical coherence tomography angiographic methods, may provide surrogate indices of relevant microvascular lesions. If so, these measures could possibly help to identify persons at high risk of dementia due to otherwise unrecognized vascular disease, possibly allowing for targeted interventions to reduce the vascular risk. Our findings support future investigation of measures in the eye that may provide surrogate indices of microvascular lesions relevant for dementia in older adults and future studies investigating if these measures may aid in clinical dementia risk prediction. Such studies should consider inclusion of variables related to diabetes control which are easily measured in the clinic (e.g., hemoglobin A1c) and important measures of small artery disease which are visible on brain MRI (e.g., white matter hyperintensities and lacunes). Given effective primary prevention strategies for stroke and other vascular diseases, better recognition of the total vascular contribution to dementia is critical for public health messaging and dementia-prevention efforts in our aging society. ARIC is a prospective observational study of 15,782 men and women from four communities in the United States. As part of the ARIC Neurocognitive study at clinic visit 5, all participants completed a full neuropsychological battery. A subset of participants (N 5 1968) also underwent brain MRI. Etiologic diagnoses were adjudicated for all participants who were diagnosed with MCI or dementia. For participants who did not attend visit 5, active dementia surveillance continued through the date of last participant contact up to September 1, 2013. Dementia diagnosis was based on a modified TICS interview with the participant, on CDR interviews with informants confirming a hospital ICD-9 discharge or death certificate dementia code, or on hospital or death certificate dementia codes alone.
Table 4 Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the relationship between retinopathy severity and CRAE (visit 3, 1993-1995) and etiologic subtype of dementia and MCI (2011-2013), Atherosclerosis Risk in Communities (ARIC) study Alzheimer’s disease related
Retinopathy severity None Mild Moderate/severe CRAE No (top 3 quartiles) Yes (bottom quartile)
Cerebrovascular related
Ndementia/MCI/Ntotal (%)
HR (95% CI)
P value
Ndementia/MCI/Ntotal (%)
HR (95% CI)
P value
663/4934 (13) 16/114 (14) 7/35 (20)
Referent 0.93 (0.56, 1.55) 1.33 (0.64, 2.77)
– 0.783 0.452
521/4792 (11) 15/113 (13) 13/41 (32)
Referent 0.99 (0.59, 1.67) 2.29 (1.24, 4.23)
– .966 .008
449/3485 (13) 159/1111 (14)
Referent 1.06 (0.88, 1.28)
– 0.578
344/3380 (10) 130/1082 (12)
Referent 1.09 (0.89, 1.34)
– .391
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRAE, central retinal arteriolar equivalent; MCI, mild cognitive impairment. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and CRAE data. FLA 5.5.0 DTD JALZ2765_proof 10 November 2018 6:00 pm ce
903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963
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Acknowledgments The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, and HHSN 2682017000021). The authors thank the staff and participants of the ARIC study for their important contributions. Dr. J.A.D. was also supported by NIH/NIA grant K01AG054693. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jalz.2018.10.002.
RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the literature using traditional (e.g., PubMed) sources. Retinal photography is thought to be a surrogate measure of microvascular changes in the brain. A small number of population-based epidemiologic studies of the relationship between retinal photography and dementia have been conducted, but these studies are primarily cross-sectional and are typically underpowered to investigate etiologic subtype. 2. Interpretation: Consistent with previous crosssectional studies, we found a positive association between two retinal signs measured in midlife—retinopathy and generalized arteriolar narrowing—and all-cause dementia over 20 years of follow-up. Retinopathy was associated strongly with cerebrovascular, but not Alzheimer’s disease-related, etiology. 3. Future directions: Although preventable, the contribution of microvascular disease to dementia may be underestimated given limitations of in vivo brain imaging. Future studies should determine if eye imaging techniques (e.g., optical coherence tomography angiography) provide valid surrogate indices of microvascular brain lesions to inform public health and clinical practice.
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Research Article
Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study Jennifer A. Deala,*, A. Richey Sharretta, Marilyn Albertb, Karen Bandeen-Rochec, Sheila Burgardd, Sonia Davis Thomase, Rebecca F. Gottesmana,b, David Knopmanf, Thomas Mosleyg, Barbara Kleinh, Ronald Kleinh a
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA b Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA c Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA d Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA e RTI International, Research Triangle Park, NC, USA f Department of Neurology, Mayo Clinic, Rochester, MN, USA g Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA h Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Abstract
Introduction: The easily-imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia. Methods: In a population-based study of 12,482 adults aged 50-73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993-1995) with incident all-cause dementia (1993-1995 to 2011-2013) and with etiologic subtype of dementia/ mild cognitive impairment (2011-13). Results: A total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/ severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36–2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09–1.45) were associated with all-cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular-related, but not Alzheimer’s-related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24–4.23). Discussion: Exploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia. Ó 2018 Published by Elsevier Inc. on behalf of the Alzheimer’s Association.
Keywords:
Cohort studies; Dementia; Diabetes; Microvasculature; Retinal; Risk factors in epidemiology
1. Introduction Vascular disease is a recognized, potentially modifiable contributor to dementia in older adults [1]. Retinal fundus photography noninvasively images small vessel changes in the eye which may resemble similar changes in the brain
*Corresponding author. Tel.: 1410-955-0491; Fax: ---. E-mail address: [email protected]
[2,3]. Retinal signs measured through fundus photography may therefore be a surrogate measure of microvasculature damage in the brain and so may be related to increased dementia risk. Retinal signs are risk factors for incident clinical stroke [4,5] and for early and largely silent cerebral changes [4,6], including ventricular enlargement [7], silent lacunesize cerebral infarcts, incident white matter lesions, and white matter hyperintensity progression [8]. However, population-based epidemiologic studies of retinal signs
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and dementia are few in number with limited prospective follow-up [9]. A recent systematic review underscored the need for future studies to describe the relationship between retinal signs and dementia subtypes [9]. We addressed this research gap using data from the Atherosclerosis Risk in Communities (ARIC) Study, a large, population-based prospective cohort, to test the hypothesis that retinal signs in midlife (1993-1995) are related to increased risk of incident all-cause dementia over 20 years (1993-1995 to 2011-2013) and to etiologic subtype of a combined outcome of dementia or mild cognitive impairment (MCI) in 2011-13.
2. Methods 2.1. Study population ARIC is a population-based prospective study of 15,792 men and women aged 45-64 years at baseline (1987-1989) from four US communities: (1) Washington County, Maryland; (2) Forsyth County, North Carolina; (3) Jackson, Mississippi; and (4) Minneapolis, Minnesota (Fig. 1) [10]. Informed consent was obtained from all participants at each visit or from a designated proxy with participant assent if the participant was unable to provide consent (e.g., known dementia diagnosis). Study procedures were approved by the Institutional Review Board for each field center. For this study, participants were excluded if race was other than black or white (N 5 48) or non-white from Minneapolis or Washington County sites (N 5 55). Also excluded were 7 participants who had a dementia diagnosis before retinal photographs were collected (visit 3, 19931995), 2882 who did not attend visit 3, and 241 who did not have an interpretable photograph. Participants were also excluded if data on retinopathy severity (N 5 4), education (N 5 19), or—given its strong relationship with retinopathy—diabetes status (N 5 54) are missing, yielding an analytic sample of 12,482. Excluded participants were older (55 vs. 54 years); more likely to be African American (45% vs. 22%); a current smoker (39% vs. 23%) and former drinker (26% vs. 17%); more likely to have diabetes (19% vs. 10%), hypertension (46% vs. 32%), and coronary heart disease (CHD) (8% vs.
4%); and more likely to die during follow-up (55% vs. 26%) than participants included in the study (Supplemental Table 1). 2.2. Diagnosis of dementia during follow-up Dementia diagnosis in this cohort has been described elsewhere [11,12] and was ascertained for all participants, including those who died during follow-up. For all participants who survived until and attended the fifth clinic visit (2011-2013; Fig. 1), diagnosis was performed using standardized algorithms incorporating longitudinal cognitive data and a complete neuropsychological battery that was administered at visit 5, with all algorithmic diagnoses confirmed by expert panel review. Dementia diagnoses for participants who did not attend visit 5 were based on a Modified Telephone Interview for Cognitive Status (TICS) interview with the participant, on modified Clinical Dementia Rating (CDR) interviews with informants confirming a hospital International Classification of Diseases, Ninth Revision (ICD-9) discharge or death certificate dementia code, or on hospital or death certificate dementia codes alone [12,13]. Active surveillance for dementia continued through the date of last participant contact up to September 1, 2013. For diagnosis ascertained by codes, the date of dementia onset was estimated to be 6 months before the hospitalization. 2.3. MCI diagnosis and etiologic subtyping of dementia and MCI at visit 5 MCI and etiologic subtype of dementia or MCI was adjudicated only for the subset of participants who attended the final clinic visit in 2011-13; the adjudication process has been previously described [11]. MCI diagnosis was based on full neuropsychological assessment at visit 5, CDR, Functional Activities Questionnaire, Neuropsychiatric Inventory, and brain magnetic resonance imaging (MRI) [11]. Alzheimer’s disease (AD) etiology was diagnosed based on the nonabrupt onset of cognitive syndrome, including memory impairment and absence of a cerebrovascular disease (CVD), Lewy body, or other (e.g., medication or alcohol induced) diagnoses [11,14,15]. CVD etiology was diagnosed based on a history of stroke with or without
• Renal Photography N=12,645
Visit 1
Visit 2
Visit 3
Visit 4
1987-89
1990-92
1993-95
1996-98
• Cognion N=15,782 N=14,214
• Cognion N=12,645
Visit 5 2011-13
Neurocognive Study (ARIC-NCS) • Full cognive baery (N=6,411) • Brain MRI (N=1,968) • Demena/MCI eology (N=2,168)
Demena Surveillance
Fig. 1. Atherosclerosis Risk in Communities (ARIC) Study Design. Abbreviations: MRI, magnetic resonance imaging; MCI, mild cognitive impairment.
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reported subsequent abrupt onset of cognitive impairment using the validated National Institute of Health Stroke Scale, evidence of stroke on neurologic examination, and small vessel disease evidenced by MRI (e.g., lacunes and white matter hyperintensities volume) [11,16]. In this analysis, AD-related dementia or MCI was defined as any case assigned an AD etiology without evidence of CVD-related etiology. CVD-related dementia or MCI was defined as any CVD etiology, with or without AD-related etiology. 2.4. Retinal exposures Photographs (visit 3) were obtained in a single, randomly selected eye for each participant by trained technicians using nonmydriatic fundus cameras. All photographs were assessed at a central reading center by trained, certified graders masked to participant characteristics, with moderate-togood intergrader reliability [17]. The presence of retinal lesions was assessed using the modified Airlie House classification, as used in the Early Treatment Diabetic Retinopathy Study [17], and retinopathy severity was classified as follows: (1) none (retinopathy severity level ,14); (2) mild (14-34); (3) moderate (35-46); and (4) severe (47). Given the small number of participants with severe retinopathy (N 5 26), retinopathy was categorized as none, mild, or moderate/severe for analysis. Microaneurysms, retinal hemorrhages (flame- and/or blot-shaped), and soft exudates were considered present if one or more “definite” signs were present. Focal arteriolar narrowing was defined as “definite” based on number and grading of arterioles estimated to be 50 mm in diameter that had a constricted area less than or equal to two-third of the width of proximal and distal vessel segments. Arteriovenous (AV) nicking was defined as “definite” based on number and grading of at least one venous blood column that was tapered on both sides of its crossing underneath an arteriole. Generalized arteriolar narrowing was evaluated using enhanced images and an imageprocessing software program. Arteriolar diameters within a prespecified zone surrounding the optic nerve were quantified as the central retinal arteriolar equivalent (CRAE) using the following formula to adjust for branching [18]. Arterioles qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Wc 5 0:87 W 2a 1 1:01 W 2b 20:22 Wa Wb 210:76 where Wc 5 the caliber of the trunk vessel Wa 5 the caliber of the smaller branch, and Wb 5 the caliber of the larger branch Generalized narrowing was defined as the lowest CRAE quartile [19]. 2.4.1. Other variables Demographic information collected at study baseline (1987-1989) includes birth date (for calculating age at study
3
visit), sex, race, and education (,high school, high school or equivalent, or .high school). Other covariates were measured when retinal photographs were collected (visit 3, 1993-1995), including smoking and drinking status, each coded as never, former, or current; body mass index (kg/ m2), calculated using measured weight and height; prehypertension, defined in persons not taking antihypertensive medication as diastolic blood pressure 80-89 mmHg or systolic blood pressure 120-139 mmHg; hypertension, defined as diastolic blood pressure 90 mmHg, systolic blood pressure 140 mmHg, or antihypertensive medication use; and diabetes defined as fasting blood glucose level 126 mg/dL, nonfasting glucose 200 mg/dL, self-reported diabetes (as diagnosed by a physician), or use of diabetes medication. CHD was defined by self-reported history at baseline and adjudicated fatal CHD, myocardial infarction, silent myocardial infarction, coronary artery bypass surgery, or angioplasty through visit 3. Prevalent stroke was defined as self-reported history of stroke diagnosed by a physician at baseline and adjudicated stroke through visit 3. Apolipoprotein (APOE) genotype was categorized as the number of ε4 Q3 alleles (0 vs. 1) [11]. 2.5. Statistical analysis Hazard ratios (HRs) of time to dementia (1993-2013) from date of retinal photography (1993-1995) comparing participants with and without retinal signs were estimated using Cox proportional hazard models. Although our surveillance methods may not identify the date of dementia onset accurately, the Cox models, as implemented, have been shown to yield similar results to a discrete time analysis (time divided into 5-year intervals) that relaxes assumptions about exact diagnosis date [12]. The proportional hazards assumption was verified by assessing correlation between scaled Schoenfeld residuals and transformed survival times, handling ties using the Efron method. Primary analyses were stratified by diabetes status, race, and APOE genotype based on a priori hypotheses, with a formal test for interaction by diabetes, race, sex, and APOE status. Analyses were adjusted for age (linear and quadratic terms), sex, an interaction between race and study site (in nonstratified models), body mass index (BMI), smoking, drinking, hypertensive status (none, prehypertension, hypertension), diabetes (in nonstratified models), CHD, and a history of stroke. In a sensitivity analysis, we adjusted for hemoglobin A1c measured at visit 2 (1990-92); hemoglobin A1c is not available at the time when the retinal photographs were taken. Missing covariate and exposure data were imputed with 20 sets of multiple imputation using chained equations (MICE) [20]. The number of imputed values for each variable is as follows: (1) AV nicking, N 5 1659; (2) focal narrowing, N 5 2169; (3) CRAE, N 5 1598; (4) microaneurysms, N 5 1581; (5) retinal hemorrhages, N 5 949; (6) soft exudates, N 5 636; (7) BMI, N 5 13; (8) drinking status, N 5 8; (9) hypertension, N 5 64; (10) CHD status,
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293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353
4
354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414
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N 5 251; and (11) stroke status, N 5 26. The imputation model included all covariates in the final model, as well as the APOE ε4 genotype, and systolic and diastolic blood pressures, cognitive function, glucose, and hemoglobin A1c measured at visit 2. To assess for a possible ascertainment bias, we repeated analyses censoring individuals after a hospitalization ICD9 code for comorbidities related to retinal signs, including ischemic heart disease (400-404) or CVD (430-438). Given the strong association of retinal signs with mortality in this cohort and to aid in the interpretation of the estimated cause-specific hazards of the relationship between retinal signs and dementia, we conducted a competingrisks sensitivity analysis using Cox proportional hazards models to compare risk of nondementia death in persons with and without retinal signs, treating dementia before death as a censoring event [21]. Studies on the relationship between retinal signs and dementia subtypes are needed [9]. However, in this cohort, etiologic subtype of dementia and MCI was adjudicated only in the subset of participants who survived until and attended the final clinic visit (visit 5). Therefore, in a secondary, complementary analysis, we used generalized linear regression with a complementary log-log link to model the HR of etiologic subtype of dementia or MCI in the subset of participants who attended visit 5 (2011-2013) with the retinal variables assessed w20 years previously (visit 3, 1993-1995). As the same etiologic classification was conducted for both MCI and dementia and because of the small numbers of events at visit 5, dementia and MCI were modeled as a joint outcome to increase stability of the results. To minimize the likelihood of a finding solely due to chance, analysis was restricted to those retinal signs that were associated with dementia in the primary model. Analyses were conducted in Stata 13 (StataCorp 2013. Stata Statistical Software: Release 13; StataCorp LP, College Station, TX). 3. Results Of 12,482 participants, 11,838 (95%), 379 (3%), and 265 (2%) were classified as having no, mild, or moderate/severe retinopathy, respectively (Table 1). Participants with moderate/severe retinopathy were more likely to be African American, less educated, never drinkers; to have hypertension, CHD and history of stroke, and greater BMI; and to die during follow-up than participants with no or mild retinopathy (Table 1). Eighty-four percent (N 5 222) of participants with moderate/severe retinopathy had diabetes compared with 13% with no retinopathy. Over a mean follow-up of 16 years, 1259 participants (10%) developed incident dementia. Twenty-five percent (N 5 310) of cases were diagnosed using visit 5 data and expert review, 44% (N 5 552) using the TICS or dementia codes confirmed by CDR, and 32% (N 5 397) using hospital or death codes alone. Seventeen percent of participants with
moderate/severe retinopathy developed dementia during the study period, as compared with 13% for mild and 10% for no retinopathy (Table 2). After full adjustment, the HR for incident dementia associated with mild (vs. no) retinopathy was 1.44 (95% confidence interval [CI]: 1.08–1.92) and that associated with moderate/severe (vs. no) retinopathy was 1.86 (95% CI: 1.36–2.55; Table 2). After adjustment for hemoglobin A1c levels, these associations were attenuated to 1.41 (95% CI: 1.05–1.88) and 1.60 (95% CI: 1.14–2.24). CRAE (narrowest quartile vs. widest three quartiles) was also associated with increased dementia risk (HR, 1.23; 95% CI: 1.07–1.41; Table 2). AV nicking and focal narrowing were not associated with dementia risk (Table 2). Available-case models that did not impute missing exposure data yielded nearly identical effect estimates (Supplemental Table 2). Retinopathy components (microaneurysms, retinal hemorrhages, and soft exudates) were independently associated with greater risk of incident dementia, although the association with soft exudates was not statistically significant (Table 2). Estimates of dementia risk associated with each retinal sign were qualitatively greater in men versus women and, with the exception of CRAE, in persons with (vs. without) diabetes (Fig. 2). However, P values for an interaction between sex and retinal signs, as well as between diabetes and retinal signs, were not significant for any retinal exposure. Mild retinopathy and CRAE were significantly associated with dementia risk in men but not in women. For mild retinopathy, the HR was 1.57 (95% CI: 1.03–2.40) in men versus 1.35 (95% CI: 0.90–2.02) in women (p-interaction 5 0.600); for CRAE, the HR was 1.37 (95% CI: 1.11–1.68) in men versus 1.15 (95% CI: 0.95–1.40) in women (p-interaction 5 0.422). Moderate/severe retinopathy was the only retinal sign in which the association was statistically significant in persons with diabetes but was not for persons without diabetes; compared with no retinopathy, moderate/ severe retinopathy was associated with a 2.14 (95% CI: 1.50–3.04) increased hazard of dementia in participants with diabetes and 1.29 (95% CI: 0.57–2.90) in participants without diabetes (p-interaction 5 0.310). We did not find statistical evidence that relationships between retinal signs and dementia differed by race or APOE ε4 allele status. In a sensitivity analysis that censored participants following a hospitalization code for CVD or ischemic heart disease, the HR for incident dementia associated with moderate/severe retinopathy was 3.34 (95% CI: 1.79–6.26), and that associated with CRAE was 1.41 (95% CI: 1.12–1.79). Overall, 23% of participants died before a dementia diagnosis during follow-up. Mortality was more common in participants with retinal signs present: (1) moderate/severe retinopathy, 51% versus 31% (mild) and 22% (none); (2) AV nicking, 30% versus 21%; focal narrowing, 29% versus 20%; and (3) CRAE, 23% versus 21% (Table 3). In a competing risks sensitivity analysis, all retinal signs except
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CRAE were associated with increased risk of death over the 20 years of follow-up. The cause-specific HR for death associated with mild (vs. no) retinopathy was 1.22 (95% CI: 1.01–1.48); moderate/severe (vs. no) retinopathy, 1.81 (95% CI: 1.50–2.17); AV nicking, 1.16 (95% CI: 1.01– 1.34); focal narrowing, 1.25 (95% CI: 1.09–1.44); and CRAE, 1.07 (95% CI: 0.97–1.18) (Table 3). Restricting to participants who attended visit 5 and excluding participants with an unknown etiologic subtype, 294 (5%) participants had dementia and 1091 (19%) had MCI. For a joint outcome of MCI and dementia, N 5 1196 (86%) had any AD-related etiologic diagnosis, of whom N 5 470 (34%) had a pure AD-related etiology and 686 (14%) had an AD-related diagnosis without evidence of CVD. Only 20 participants had a pure CVDrelated etiology and N 5 549 had a primary or secondary
5
etiologic CVD diagnosis. In fully adjusted models, moderate/severe retinopathy was associated with increased risk of MCI/dementia with cerebrovascular, but not AD, etiology. The HR comparing moderate/severe with no retinopathy was 1.33 (95% CI: 0.64–2.77) for AD-related dementia or MCI without evidence of CVD and 2.29 (95% CI: 1.24–4.23) for MCI or dementia with any cerebrovascular etiology (Table 4). No associations were found for CRAE and either etiologic subtype. 4. Discussion In this study of 12,482 men and women (aged 50-73 years, 22% African American), two retinal signs—retinopathy severity and CRAE, markers of small vessel integrity and vessel wall integrity and dimensions, respectively—were
Table 1 Baseline (visit 3, 1993-1995) characteristics by retinopathy severity, Atherosclerosis Risk in Communities (ARIC) study (N 5 12,482)
Q6
Retinopathy severity
y
Age (years) Black race Female Education ,High school High school .High school Body mass index (kg/m2)y Smoking status Never Former Current Drinking status Never Former Current Diabetes Hypertension No hypertension Prehypertension Hypertension Stroke Coronary heart disease APOE ε4 genotype 0 ε4 alleles 1 ε4 alleles Follow-up status Died during follow-up Living, did not attend visit 5 Attended visit 5 (2011-13) Follow-up timey Other retinal measures Arteriovenous (AV) nicking Focal arteriolar narrowing CRAE (lowest quartile)
Total (N 5 12,482)
None (N 5 11,838)
Mild (N 5 379)
Moderate/severe (N 5 265)
N (%)
N (%)
N (%)
N (%)
P value*
60.5 (5.7) 2782 (22) 6929 (56)
60.4 (5.7) 2519 (21) 6580 (56)
60.7 (5.7) 134 (35) 200 (53)
61.1 (5.7) 129 (49) 149 (56)
.070 ,.0001 .540
2498 (20) 5229 (42) 4755 (38) 28.5 (5.5)
2302 (19) 4987 (42) 4549 (38) 28.4 (5.4)
97 (26) 150 (40) 132 (35) 29.4 (5.8)
99 (37) 92 (35) 74 (28) 31.4 (6.9)
,.0001
5115 (41) 5158 (41) 2196 (18)
4841 (41) 4897 (41) 2088 (18)
155 (41) 154 (41) 69 (18)
119 (45) 107 (40) 39 (15)
.651
3073 (25) 2851 (23) 6545 (52) 1905 (15)
2873 (24) 2654 (22) 6301 (53) 1581 (13)
108 (29) 102 (27) 166 (44) 102 (27)
92 (35) 95 (36) 78 (29) 222 (84)
,.0001
4289 (35) 3064 (25) 5065 (41) 232 (2) 868 (7)
4167 (35) 2947 (25) 4665 (40) 203 (2) 794 (7)
88 (23) 75 (20) 212 (57) 14 (4) 38 (10)
34 (13) 42 (16) 188 (71) 15 (6) 36 (14)
84,162 (70) 3662 (30)
7991 (70) 3461 (30)
244 (66) 125 (34)
181 (70) 76 (30)
.312
3234 (26) 3224 (26) 6024 (48) 15.6 (4.4)
2936 (25) 3069 (26) 5833 (49) 15.7 (4.3)
136 (36) 107 (28) 136 (36) 14.6 (5.0)
162 (61) 48 (18) 55 (21) 12.2 (5.9)
,.0001
1641 (14) 1688 (15) 2741 (25)
1502 (14) 1538 (14) 2596 (25)
71 (19) 96 (27) 92 (25)
68 (27) 54 (22) 53 (24)
,.0001 ,.0001 .900
Abbreviations: APOE, apolipoprotein E; CRAE, central retinal arteriolar equivalent. *P-values from one-way analysis of variance test or Kruskal-Wallis test (continuous variables) or Pearson’s chi2 test (categorical variables). y Values expressed as mean (SD).
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,.0001
,.0001 ,.0001 ,.0001 ,.0001
,.0001
537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597
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6
598 599 600 601Q7 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658
Table 2 Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the relationship between retinal signs (visit 3, 1993-1995) and incident all-cause dementia (1993-2013), Atherosclerosis Risk in Communities (ARIC) study Incident dementia HR Ndementia/Ntotal (%) (95% CI) Retinopathy severity None Mild Moderate/severe Retinopathy components Microaneurysms No Yes Retinal hemorrhages No Yes Soft exudates No Yes Arteriovenous nicking No Yes Focal narrowing No Yes CRAE No (top 3 quartiles) Yes (bottom quartile)
P value
1165/11,838 (10) 48/379 (13) 46/265 (17)
Referent – 1.44 (1.08, 1.92) .014 1.86 (1.36, 2.55) ,.0001
986/10,421 (9) 71/480 (15)
Referent – 1.61 (1.25, 2.07) ,.0001
1073/11,151 (10) 65/382 (17)
Referent – 1.81 (1.40, 2.35) ,.0001
1151/11,688 (10) 21/158 (13)
Referent 1.40 (0.89, 2.19)
– .145
958/10,154 (9) 74/669 (11)
Referent 1.11 (0.88, 1.39)
– .389
865/9505 (9) 98/808 (12)
Referent 1.17 (0.94, 1.45)
– .161
749/8143 (9) 298/2741 (11)
Referent 1.23 (1.07, 1.41)
– .004
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRAE, central retinal arteriolar equivalent. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and exposure data.
independently associated with increased risk of all-cause dementia over 20 years. In analyses adjusted for demographic and clinical covariates, we observed a dose-dependent association between retinopathy severity (none, mild, and moderate/severe) and dementia, with the strongest association observed for moderate/severe (vs. none) retinopathy; p-trend ,0.0001. Similar associations were observed for retinopathy components (microaneurysms, retinal hemorrhages, and soft exudates), although the association for soft exudates was not statistically significant, likely due to limited sample size (N 5 158 participants with soft exudates). Among the 25% of participants with the narrowest retinal arterioles as measured by CRAE, the risk of dementia was increased by 23%. The relationship between moderate/severe retinopathy and dementia was stronger for persons with diabetes than for persons without diabetes (HR, 2.14 vs. 1.29). This might suggest that moderate/severe retinopathy is a marker for diabetes severity, rather than a specific marker for microvascular disease in the brain. However, the number of participants in this study who have moderate/severe retinopathy but not diabetes was small (N 5 43), limiting precision
of the estimate in the group without diabetes. In addition, in a sensitivity analysis that adjusted for hemoglobin A1c, a marker of long-term hyperglycemia, moderate/severe retinopathy remained associated with dementia during followup, although the effect estimate was attenuated by 14%; it is a limitation of this study that hemoglobin A1c was not measured concurrently with the retinal photographs but at an average of 3 years before the time when the retinal photographs were taken. Our primary analysis used a dementia diagnosis that incorporated multiple data sources. For the majority of participants, dementia was diagnosed using a standardized algorithm and expert panel review using up to 20 years of longitudinal cognitive data, including a full neuropsychological battery administered at the fifth clinic visit (2011-2013). However, because those who survived and attended visit 5 were a select group (for example, 79% of participants with moderate/severe retinopathy did not attend visit 5; Table 1), we ascertained dementia cases which occurred before the final clinic visit using community-wide hospital and death certificate surveillance. Use of this surveillance data permits our examining early dementias, which, as was reported previously [13], are the cases most strongly associated with classical vascular risk factors. An important concern with using dementia cases ascertained in this manner is that the risk of hospitalization (therefore ascertainment and diagnosis) may be related to the exposure, which could therefore result in overestimation of the association between retinal signs and dementia. However, retinop- Q4 athy- and CRAE-dementia associations were even stronger when participants were censored after hospitalization for ischemic heart disease or CVD (HR, 3.34 and 1.41, respectively) and when cases diagnosed by only hospital or death certificate codes were excluded (OR, 2.53 and 1.26, respectively), suggesting that our findings are not only due to ascertainment bias or misclassification of dementia. In our primary analysis, we estimated the cause-specific HR for dementia before death, comparing participants with and without retinal signs. Inferences from this model type are appropriate and useful for etiologic research questions but should not be interpreted as the effect of retinal signs on the absolute risk of the dementia over time, as the latter inference is dependent on the survival function, both for dementia and for death. To aid in the interpretation of our findings, we conducted a competing risks analysis to estimate the cause-specific hazard of death before dementia. Estimated associations for retinopathy were strong for both dementia and death. Although we found no association between AV nicking and focal narrowing and dementia, both signs were related to death before a dementia diagnosis. In our study, MCI and etiologic diagnosis of both MCI and dementia were adjudicated using the full neuropsychological battery and MRI brain imaging administered only at visit 5. Consistent with the hypothesis that fundus photography may provide insight into small vessel brain disease, we found that moderate/severe (vs. none) retinopathy was
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659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719
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720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780
Retinopathy: Moderate/Severe
A
P-interaction: 0.310
Diabetes
0.760 Black race
0.517
N=10577
0.461
0.508
0.869
No Diabetes
N=9700 0.5 1.0 1.5 2.0 2.5 3.0
C
0.5 1.0 1.5 2.0 2.5 3.0
P-interaction: 0.600
Females
0.759
N=6929
0.750 ≥1 ε4 alleles
0.405
N=3662
0.598
Focal Narrowing CRAE
P-interaction: 0.631
D
0.933
Mild AV Nicking
0.802
White race
N=1905
Retinopathy: Moderate/Severe
0.818
N=2782
Focal Narrowing CRAE
P-interaction: 0.470
0.613
Mild AV Nicking
B
7
0.422
Males N=5553
0.502 0.799
No ε 4 alleles N=8416
0.5 1.0 1.5 2.0 2.5 3.0
0.5 1.0 1.5 2.0 2.5 3.0
Hazard Ratio (95% CI)
Hazard Ratio (95% CI)
Fig. 2. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) of the relationship between retinal signs (visit 9, 1993-1995) and incident dementia (1993-2015) by diabetes status, race, sex, and number of APOE ε4 alleles, Atherosclerosis Risk in Communities (ARIC) Study adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This figure includes imputed values for missing exposure and covariate data. (A) Results stratified by diabetes status (N 5 12,482). (B) Results stratified by race (N 5 12,482). (C) Results stratified by sex (N 5 12,482). (D) Results stratified by number of APOE ε4 alleles (N 5 12,078). Abbreviations: AV, arteriovenous; CRAE, central retinal arteriolar equivalent; BMI, body mass index; CHD, coronary heart disease; APOE, apolipoprotein E.
associated with a joint outcome of MCI and dementia for cerebrovascular-related etiologies (primary or secondary), but not for AD-related etiology without evidence of CVD. Although limitations in the study design did not allow for the most appropriate methods to handle censoring for this research question (i.e., measures used to adjudicate etiology were only collected at one point in time), this secondary analysis does address an important research gap—that of the relationship between retinal signs and etiologic subtype of dementia [9]—and, given the strong association with retinal signs and mortality, may be a conservative estimate of the relationship between retinal signs and the cerebrovascular subtype. These findings should be replicated in a study with dementia etiology adjudicated at more than one time point. Only one prospective study (Rotterdam) with similar retinal measures to ARIC has been published on this topic. Unlike our study, no associations were reported. Neither baseline retinopathy (age and sex-adjusted OR: 1.2, 95% CI: 0.9–1.5; N 5 6078) [22] nor CRAE (OR: 1.05, 95% CI: 0.96–1.16; N 5 5553) [23] were associated with dementia risk over a mean follow-up of 11 years. The potential use of fundus photography for differentiating dementia subtypes using large, well-powered study populations was highlighted in a recent systematic review [9]. Our study addresses this research gap with a large sample size in a biracial popula-
tion, retinal signs measured in midlife with up to 20 years of follow-up, and well-characterized dementia and MCI etiologic outcomes. Methodologically, we accounted for potential bias due to missing covariate data with multiple imputation and assessed the robustness of our findings to ascertainment bias in sensitivity analysis. One minor limitation of our study is that retinal photographs were taken in only one (randomly selected) eye; although we do not expect differences between the left and right eyes, having both eyes would potentially allow for more accurate ascertainment of the presence of retinal signs. An additional limitation of this analysis is that retinal photographs were only measured at only one time point. Unmeasured and residual confounding is a threat to inference in any observational epidemiologic study. However, covariates found to be associated in prior analyses of dementia risk in this cohort which may also be related to retinal signs have been included in this analysis and defined similarly to prior investigations [12]. This study documented an association of two midlife retinal signs—retinopathy and generalized arteriolar narrowing (measured as CRAE)—with greater 20-year risk of all-cause dementia in 12,482 men and women from four US communities. This association was observed for both white and black participants, and it did not differ by APOE ε4 genotype. Retinopathy associations were significant
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Table 3 Competing risk analysis of the relationship between retinal signs (visit 3, 1993-1995) and mortality (1993-2013), Atherosclerosis Risk in Communities (ARIC) study
Retinopathy severity None Mild Moderate/severe Retinopathy components Microaneurysms No Yes Retinal hemorrhages No Yes Soft exudates No Yes Arteriovenous nicking No Yes Focal narrowing No Yes CRAE No (top 3 quartiles) Yes (bottom quartile)
Deaths Ndeaths/Ntotal (%)
HR (95% CI)
P value
2560/11,838 (22) 116/379 (31) 136/265 (51)
Referent 1.22 (1.01, 1.48) 1.81 (1.50, 2.17)
– .035 ,.0001
2135/10,421 (20) 198/480 (41)
Referent 1.51 (1.30, 1.76)
– ,.0001
2344/11,151 (21) 184/382 (48)
Referent 1.74 (1.48, 2.04)
– ,.0001
2532/11,688 (22) 80/158 (51)
Referent 1.82 (1.45, 2.29)
– ,.0001
2098/10,154 (21) 199/669 (30)
Referent 1.16 (1.01, 1.34)
– .040
1919/9505 (20) 235/808 (29)
Referent 1.25 (1.09, 1.44)
– .002
1703/8143 (21) 629/2741 (23)
Referent 1.07 (0.97, 1.18)
– .151
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CI, confidence interval; CRAE, central retinal arteriolar equivalent; HR, hazard ratio. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and exposure data.
only in persons with diabetes, but the converse was true for CRAE—associations were strongest in persons without diabetes. In analyses of midlife retinal signs and etiologic diagnoses of MCI and dementia adjudicated 20 years later, retinopathy was associated with cerebrovascular-related, but not Alzheimer’s-related, impairments in the absence of CVD. Future studies should investigate the mechanism underlying these relationships.
The extent of the microvascular contribution to the development of dementia may be unrecognized because of the inability to visualize the brain microvasculature in vivo [24–28]. However, fundus photography and emerging, more sensitive, imaging techniques in the eye, such as optical coherence tomography angiographic methods, may provide surrogate indices of relevant microvascular lesions. If so, these measures could possibly help to identify persons at high risk of dementia due to otherwise unrecognized vascular disease, possibly allowing for targeted interventions to reduce the vascular risk. Our findings support future investigation of measures in the eye that may provide surrogate indices of microvascular lesions relevant for dementia in older adults and future studies investigating if these measures may aid in clinical dementia risk prediction. Such studies should consider inclusion of variables related to diabetes control which are easily measured in the clinic (e.g., hemoglobin A1c) and important measures of small artery disease which are visible on brain MRI (e.g., white matter hyperintensities and lacunes). Given effective primary prevention strategies for stroke and other vascular diseases, better recognition of the total vascular contribution to dementia is critical for public health messaging and dementia-prevention efforts in our aging society. ARIC is a prospective observational study of 15,782 men and women from four communities in the United States. As part of the ARIC Neurocognitive study at clinic visit 5, all participants completed a full neuropsychological battery. A subset of participants (N 5 1968) also underwent brain MRI. Etiologic diagnoses were adjudicated for all participants who were diagnosed with MCI or dementia. For participants who did not attend visit 5, active dementia surveillance continued through the date of last participant contact up to September 1, 2013. Dementia diagnosis was based on a modified TICS interview with the participant, on CDR interviews with informants confirming a hospital ICD-9 discharge or death certificate dementia code, or on hospital or death certificate dementia codes alone.
Table 4 Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the relationship between retinopathy severity and CRAE (visit 3, 1993-1995) and etiologic subtype of dementia and MCI (2011-2013), Atherosclerosis Risk in Communities (ARIC) study Alzheimer’s disease related
Retinopathy severity None Mild Moderate/severe CRAE No (top 3 quartiles) Yes (bottom quartile)
Cerebrovascular related
Ndementia/MCI/Ntotal (%)
HR (95% CI)
P value
Ndementia/MCI/Ntotal (%)
HR (95% CI)
P value
663/4934 (13) 16/114 (14) 7/35 (20)
Referent 0.93 (0.56, 1.55) 1.33 (0.64, 2.77)
– 0.783 0.452
521/4792 (11) 15/113 (13) 13/41 (32)
Referent 0.99 (0.59, 1.67) 2.29 (1.24, 4.23)
– .966 .008
449/3485 (13) 159/1111 (14)
Referent 1.06 (0.88, 1.28)
– 0.578
344/3380 (10) 130/1082 (12)
Referent 1.09 (0.89, 1.34)
– .391
Abbreviations: BMI, body mass index; CHD, coronary heart disease; CRAE, central retinal arteriolar equivalent; MCI, mild cognitive impairment. Adjusted for age (linear and quadratic terms), education, sex, race*center interaction, BMI, drinking status, smoking status, diabetes, hypertensive status, CHD, and history of stroke. This table includes imputed values for missing covariate and CRAE data. FLA 5.5.0 DTD JALZ2765_proof 10 November 2018 6:00 pm ce
903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963
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964 965 966 967 968 969 970 971 972 973 974 975Q5 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024
Acknowledgments The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, and HHSN 2682017000021). The authors thank the staff and participants of the ARIC study for their important contributions. Dr. J.A.D. was also supported by NIH/NIA grant K01AG054693. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jalz.2018.10.002.
RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the literature using traditional (e.g., PubMed) sources. Retinal photography is thought to be a surrogate measure of microvascular changes in the brain. A small number of population-based epidemiologic studies of the relationship between retinal photography and dementia have been conducted, but these studies are primarily cross-sectional and are typically underpowered to investigate etiologic subtype. 2. Interpretation: Consistent with previous crosssectional studies, we found a positive association between two retinal signs measured in midlife—retinopathy and generalized arteriolar narrowing—and all-cause dementia over 20 years of follow-up. Retinopathy was associated strongly with cerebrovascular, but not Alzheimer’s disease-related, etiology. 3. Future directions: Although preventable, the contribution of microvascular disease to dementia may be underestimated given limitations of in vivo brain imaging. Future studies should determine if eye imaging techniques (e.g., optical coherence tomography angiography) provide valid surrogate indices of microvascular brain lesions to inform public health and clinical practice.
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