Ocular Biomarkers for Alzheimer Disease Dementia

Abstract

ImportanceSeveral ocular biomarkers have been proposed for the early detection of Alzheimer disease (AD) and mild cognitive impairment (MCI), particularly fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA).ObjectiveTo perform an umbrella review of systematic reviews to assess the diagnostic accuracy of ocular biomarkers for early diagnosis of Alzheimer disease.Data SourcesMEDLINE, Embase, and PsycINFO were searched from January 2000 to November 2021. The references of included reviews were also searched.Study SelectionSystematic reviews investigating the diagnostic accuracy of ocular biomarkers to detect AD and MCI, in secondary care or memory clinics, against established clinical criteria or clinical judgment.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline checklist was followed and the Risk Of Bias in Systematic reviews tool was used to assess review quality.Main Outcomes and MeasuresThe prespecified outcome was the accuracy of ocular biomarkers for diagnosing AD and MCI. The area under the curve (AUC) was derived from standardized mean difference.ResultsFrom the 591 titles, 14 systematic reviews were included (median [range] number of studies in each review, 14 [5-126]). Only 4 reviews were at low risk of bias on all Risk of Bias in Systematic Reviews domains. The imaging-derived parameters with the most evidence for detecting AD compared with healthy controls were OCT peripapillary retinal nerve fiber layer thickness (38 studies including 1883 patients with AD and 2510 controls; AUC = 0.70; 95% CI, 0.53-0.79); OCTA foveal avascular zone (5 studies including 177 patients with AD and 371 controls; AUC = 0.73; 95% CI, 0.50-0.89); and saccadic eye movements prosaccade latency (30 studies including 651 patients with AD/MCI and 771 controls; AUC = 0.64; 95% CI, 0.58-0.69). Antisaccade error was investigated in fewer studies (12 studies including 424 patients with AD/MCI and 382 controls) and yielded the best accuracy (AUC = 0.79; 95% CI, 0.70-0.88).Conclusions and RelevanceThis umbrella review has highlighted limitations in design and reporting of the existing research on ocular biomarkers for diagnosing AD. Parameters with the best evidence showed poor to moderate diagnostic accuracy in cross-sectional studies. Future longitudinal studies should investigate whether changes in OCT and OCTA measurements over time can yield accurate predictions of AD onset.

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia

“…67 Repeated, non-invasive measures will also be possible using eye imaging, where deposition of Aβ and tau, atrophy of neuronal layers, and vascular changes could all be potentially monitored. 34,77 Most of the current prognostic biomarkers for AD were discovered through hypothesis-driven research using conventional statistical approaches to predict disease outcomes. However, AI algorithms have been gaining traction as an alternative approach for prediction, and combining biomarkers from multiple modalities, such as a CSF, MRI, and cognitive performance biomarkers, has been shown in recent studies to improve model performance.…”

“…New markers can then be tested in other modalities such as blood plasma 67 . Repeated, non‐invasive measures will also be possible using eye imaging, where deposition of Aβ and tau, atrophy of neuronal layers, and vascular changes could all be potentially monitored 34,77 …”

An Eye on Clinical Translation—Considerations for Research Into Ocular Biomarkers of Alzheimer Disease and Related Dementias

“…In recent years, the number of systematic reviews and meta-analyses has grown, too, and the umbrella review presented in this issue is a timely effort to synthesize evidence from across these numerous investigations. 2 The umbrella review presents several key points that are pertinent for research into ocular biomarkers of ADRDs, particularly regarding these biomarkers' translation to the clinical setting. One key takeaway is that cross-sectional measures of retinal parameters may not be as effective as longitudinal assessments at distinguishing people with MCI or AD.…”

“…Consequently, there has been a burgeoning body of research investigating differences in ocular parameters between people with AD, mild cognitive impairment (MCI), and healthy controls. In recent years, the number of systematic reviews and meta-analyses has grown, too, and the umbrella review presented in this issue is a timely effort to synthesize evidence from across these numerous investigations …”

“…As Costanzo et al report, many of the systematic reviews did not report the diagnostic criteria used by the studies they included and pooled groups across studies using different diagnostic methods. It is possible that differences in diagnostic methods contributed to the moderate to poor performance of many of the ocular biomarkers.…”