Reticular pseudodrusen load is associated with an increased risk of stroke.
Clinical Snapshot
PICO Framework
| P — Population | UK Biobank participants aged middle-to-older age (n=2010) with retinal imaging data, categorised into those with reticular pseudodrusen (RPD), drusen, both, or neither (controls) |
| I — Intervention | Exposure: presence and quantified load of reticular pseudodrusen (RPD) on optical coherence tomography (OCT), identified via a validated deep learning framework |
| C — Comparator | Controls (no RPD, no drusen; n=1170) and participants with pure drusen (n=401) |
| O — Outcomes | Primary: stroke; Secondary: myocardial infarction (MI); Combined MI/stroke — all ascertained from UK Biobank health records |
Bottom Line
This retrospective analysis of UK Biobank data reports a statistically significant association between quantified reticular pseudodrusen (RPD) load on OCT and stroke risk, independent of age, sex, lipid profile, and smoking. At the mean RPD count of 199 lesions, the authors estimate approximately 20% increased stroke odds. However, several methodological limitations temper enthusiasm for immediate clinical translation. The confidence interval barely excludes the null (OR 1.00–1.04, p=0.042), the pure RPD group is small (n=71), and the confounder adjustment is incomplete — notably absent are hypertension, diabetes, atrial fibrillation, and BMI, all of which are available in UK Biobank and are major stroke determinants. The cross-sectional design prevents establishing temporality, and stroke subtype was not reported. The absence of any MI association, despite the proposed shared vascular mechanism, is biologically inconsistent and warrants explanation. These findings are hypothesis-generating rather than practice-changing. Clinicians should be aware that RPD may signal systemic vascular vulnerability, but formal cardiovascular risk screening protocols based on RPD load cannot be recommended until prospective, adequately powered studies with comprehensive confounder adjustment confirm these associations.
Key Findings
P Value: p=0.042 (multivariable); p=0.028 (univariable)
Effect Size: OR 1.02 per 20 RPD lesions (adjusted for age, sex, HDL/LDL ratio, smoking). No significant association between drusen and stroke, or between RPD/drusen and MI.
Primary Outcome: Association between RPD load and stroke risk: adjusted OR 1.02 per 20 RPD lesions (p=0.042). At mean RPD load of 199 lesions, authors estimate approximately 20% increased stroke risk.
Nnt Or Sensitivity: No NNT calculable from available data. Absolute stroke risk difference not reported. The OR of 1.02 per 20-lesion increment represents a very small per-unit effect; clinical significance depends on absolute baseline stroke risk in this population, which is not provided.
Confidence Interval: 95% CI: 1.00 to 1.04
Clinical Application
RPD quantification currently requires specialised deep learning software not routinely available in standard clinical OCT platforms. Manual RPD counting is time-consuming and subject to inter-observer variability. Until automated quantification tools are integrated into commercial OCT devices, routine RPD load assessment for cardiovascular risk stratification is not immediately feasible in most clinical settings. The finding that RPD presence (rather than precise load) may signal elevated stroke risk is more immediately actionable. In Australia, AMD affects approximately 1 in 7 people over 50 years, with RPD increasingly recognised as a distinct and prognostically important phenotype. Ophthalmologists and optometrists routinely perform OCT imaging in this population. If validated, these findings would support referral pathways between eye care providers and general practitioners or cardiologists for cardiovascular risk assessment in patients with high RPD burden. The RACGP guidelines on cardiovascular risk management (including the Australian Cardiovascular Risk Calculator) do not currently incorporate retinal phenotype data. TGA-approved OCT devices are widely available in Australian ophthalmology practices. PBS-listed anti-VEGF therapies for neovascular AMD already create regular OCT monitoring opportunities where RPD could be systematically identified. Prospective Australian validation studies, ideally within the 45 and Up Study or similar cohorts with linked health data, would be valuable. Ethnic diversity considerations are important, as UKBB findings may not fully translate to Australia's Indigenous, Asian, and Pacific Islander populations. Older adults (middle-aged to elderly) undergoing retinal OCT imaging, particularly those with AMD or suspected AMD, in whom RPD are identified. Most relevant to ophthalmologists, optometrists, and general practitioners managing patients with AMD-spectrum disease.
Abstract
BACKGROUND/AIMS: Reticular pseudodrusen (RPD) are increasingly recognised as a distinct phenotype in the age-related macular degeneration (AMD) disease spectrum. This study investigates the association between RPD and cardiovascular outcomes, specifically myocardial infarction (MI) and stroke in the UK Biobank (UKBB). METHODS: Retrospective analysis of UKBB participants (n=2010). A validated deep learning framework identified and quantified subjects with RPD, drusen and controls on optical coherence tomography. Five retina specialists validated the artificial intelligence findings. Multivariable logistic regression models assessed the association between RPD/drusen and stroke, MI and combined MI/stroke, adjusting for age, sex, high-density lipoprotein cholesterol/low-density lipoprotein cholesterol ratio and smoking history. RESULTS: The study cohort included 71 subjects with pure RPD, 401 with pure drusen, 368 with both and 1170 controls. Univariable analysis showed that for every 20 RPD lesions, the OR for stroke increased by 1.02 (95% CI 1.00 to 1.04, p=0.028). The mean number of RPD per patient in this cohort was 199, indicating an increased stroke risk of 20%. Multivariable analysis showed a significant association between RPD load and stroke risk (OR 1.02, 95% CI 1.00 to 1.04, p=0.042) after adjustment for confounders. No significant association was found between drusen and stroke or between RPD/drusen and MI. CONCLUSION: Increased RPD load is associated with a higher risk of stroke, independent of traditional cardiovascular risk factors. Drusen did not have similar associations, suggesting that RPD may represent a distinct disease entity. Evaluating cardiovascular risk in patients with numerous RPD might be advisable. Further prospective studies are needed to validate these findings and explore the underlying mechanisms.
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