Klein, Ronald

Introduction: The microvascular contribution to dementia may be under-recognized because of the inability to visualize the brain microvasculature in vivo. Although the easily-imaged retinal vasculature may be a surrogate measure for that in the brain, large prospective studies of the relationship between retinal vascular signs and dementia are scarce. Hypothesis: Retinal signs are associated with greater subsequent risk of all-cause dementia and etiologic subtype over 20 years in 12482 men and women (mean age of 60 years when retinal signs were measured, 22% African American). Methods: Retinal signs were measured using fundus photography (1993-1995). Presence and etiology of dementia and mild cognitive impairment (MCI) were adjudicated using data collected in 2011-13, including a complete neuropsychological battery and brain magnetic resonance imaging (subset of participants). For participants not attending the 2011-13 visit, dementia cases were identified using the Telephone Interview for Cognitive Status–Modified or informant interview, or by hospitalization or death certificate code. Multivariable-adjusted Cox proportional hazards models and logistic regression were used to quantify the relationship of retinal signs with dementia risk and with etiologic subtype, respectively. Results: During a mean 16 years of follow-up, 1259 (10%) participants developed dementia. Moderate or severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% CI: 1.36, 2.55) and generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles), (HR, 1.26; 95% CI: 1.09, 1.45) were associated with all-cause dementia. Results did not differ by diabetes, race or APOE ε4 genotype. Retinopathy was associated with cerebrovascular-related dementia and MCI (odds ratio, 2.66; 95% CI: 1.30, 5.42). Conclusions: Retinal photography captures small vascular signs in the eye that are related to increased dementia risk. Emerging techniques, such as optical coherence tomography angiography, may have the sensitivity to provide surrogate indices of microvascular lesions relevant to dementia in older adults.

AbstractIntroductionThe easily‐imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia.MethodsIn 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).ResultsA 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 disease–related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24–4.23).DiscussionExploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia.

Background and Purpose— Brain microvascular disease leads to leukoaraiosis and lacunar infarcts and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown. Methods— Eight hundred thirty participants in the Atherosclerosis Risk in Communities (ARIC) study aged ≥55 years and without previous stroke received an initial brain magnetic resonance imaging, retinal photography, and, 10 years later, a follow up magnetic resonance imaging. We evaluated retinal vascular sign phenotypes as predictors of (1) leukoaraiosis volume increase, and (2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes mellitus were evaluated as confounders and effect modifiers. Results— Individuals with any retinopathy (3.34 cm 3 ; 95% confidence interval [CI], 0.74–5.96) or with arteriovenous nicking (2.61 cm 3 ; 95% CI, 0.80–4.42) each had greater progression of leukoaraiosis compared with those without these conditions. Any retinopathy (odds ratio [OR], 3.18; 95% CI, 1.71–5.89) or its components—microaneurysms (OR, 3.06; 95% CI, 1.33–7.07) and retinal hemorrhage (OR, 3.02; 95% CI, 1.27–7.20)—as well as arteriovenous nicking (OR, 1.93; 95%, CI 1.24–3.02) and focal arteriolar narrowing (OR, 1.76; 95% CI, 1.19–2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes. Conclusions— A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease, which have not been shown before.

A major goal of the study was to assess the methodologies available for the quantification of retinal lesions suitable for application in trials of metabolic management. We describe the methods used for grading stereoscopic color fundus photographs. Overall retinopathy severity level for each eye ranging from normal (level 10) to high-risk category (level 70) was assigned on the basis of gradings of individual lesions. Change in retinopathy severity level over the 8-mo period was detected in 3–62% of patients, depending on the method used and the definition of change. Lesions responsible for change in level were mainly retinal infarcts (soft exudates) and intraretinal microvascular abnormalities.

OBJECTIVE To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired HbA1c [IA1C]) than in healthy subjects (non-IG). RESEARCH DESIGN AND METHODS Matched IG and non-IG volunteers were randomly identified from population-based diagnostic and laboratory registries, restudied, and reclassified as non-IG (n = 150), IG (n = 174), or new diabetes (n = 218). RESULTS Frequency (%) of DPN in non-IG, IG, and new diabetes was 3 (2.0%), 3 (1.7%), and 17 (7.8%) narrowly defined (no other cause for polyneuropathy) and 19 (12.7%), 22 (12.6%), and 38 (17.4%) broadly defined. Mean and frequency distribution of composite scores of nerve conduction and quantitative sensation tests were not significantly different between IG and non-IG but were worse in new diabetes. Frequency of retinopathy and nephropathy was significantly increased only in new diabetes. In secondary analysis, small but significant increases in retinopathy and nephropathy were found in IGT, IFG, and IGT combined groups. CONCLUSIONS In population studies of Olmsted County, Minnesota, inhabitants, prevalence of typical DPN, retinopathy, and nephropathy was significantly increased only in subjects with new diabetes—not in subjects with IG as defined by American Diabetes Association (ADA) criteria of abnormality of IFG, IGT, or IA1C. For atypical DPN, such an increase was not observed even in subjects with new diabetes. In medical practice, explanations other than IG should be sought for patients with atypical DPN (chronic idiopathic axonal polyneuropathy) who have IG.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 −75 ), ARMS2 ( P < 10 −59 ), C2/CFB ( P < 10 −20 ), C3 ( P < 10 −9 ), and CFI ( P < 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.