Retinal mid-peripheral capillary free zones are enlarged in cognitively unimpaired older adults at high risk for Alzheimer’s disease

Abstract

Background Compared to standard neuro-diagnostic techniques, retinal biomarkers provide a probable low-cost and non-invasive alternative for early Alzheimer’s disease (AD) risk screening. We have previously quantified the periarteriole and perivenule capillary free zones (mid-peripheral CFZs) in cognitively unimpaired (CU) young and older adults as novel metrics of retinal tissue oxygenation. There is a breakdown of the inner retinal blood barrier, pericyte loss, and capillary non-perfusion or dropout in AD leading to potential enlargement of the mid-peripheral CFZs. We hypothesized the mid-peripheral CFZs will be enlarged in CU older adults at high risk for AD compared to low-risk individuals. Methods 20 × 20° optical coherence tomography angiography images consisting of 512 b-scans, 512 A-scans per b-scan, 12-µm spacing between b-scans, and 5 frames averaged per each b-scan location of the central fovea and of paired major arterioles and venules with their surrounding capillaries inferior to the fovea of 57 eyes of 37 CU low-risk (mean age: 66 years) and 50 eyes of 38 CU high-risk older adults (mean age: 64 years; p = 0.24) were involved in this study. High-risk participants were defined as having at least one APOE e4 allele and a positive first-degree family history of AD while low-risk participants had neither of the two criteria. All participants had Montreal Cognitive Assessment scores ≥ 26. The mid-peripheral CFZs were computed in MATLAB and compared between the two groups. Results The periarteriole CFZ of the high-risk group (75.8 ± 9.19 µm) was significantly larger than that of the low-risk group (71.3 ± 7.07 µm), p = 0.005, Cohen’s d = 0.55. The perivenule CFZ of the high-risk group (60.4 ± 8.55 µm) was also significantly larger than that of the low-risk group (57.3 ± 6.40 µm), p = 0.034, Cohen’s d = 0.42. There were no significant differences in foveal avascular zone (FAZ) size, FAZ effective diameter, and vessel density between the two groups, all p > 0.05. Conclusions Our results show larger mid-peripheral CFZs in CU older adults at high risk for AD, with the potential for the periarteriole CFZ to serve as a novel retinal vascular biomarker for early AD risk detection.

Quantifying Putative Retinal Gliosis in Preclinical Alzheimer's Disease

“…Our results of a better multimodal model distinguishing between preclinical AD and controls are consistent with findings of our previous study that investigated a multimodal model of the mid-peripheral capillary free zones and other vascular metrics for early AD risk detection. 17 It is also consistent with results of a previous study that investigated a multimodal model of fractal and lacunarity analysis to distinguish between cognitively impaired and CU older adults. 82 …”

“…However, most blood-based biomarkers do not do well in early AD probably due to the fact that, unlike the retina, which is a direct extension of the brain, blood-based biomarkers are derived via a downstream effect from the CNS and can be influenced by genetic factors and renal function. 17 Elevated levels of glial fibrillary acidic protein (GFAP), an astrocytic protein signifying astrogliosis, have been identified in blood samples and linked to preclinical AD. 12 Additionally, plasma levels of Aβ42/Aβ40 ratio and p-tau 217 are elevated in individuals with preclinical AD.…”

“…1 C). 17 These three en face slabs were obtained from the dense volume SD-OCT scans using the vendor software. The MLC layer en face image has previously been defined via adaptive optics OCT (AO-OCT) imaging as having the highest density of glial structures.…”

“…As an extension of the brain, 15 , 16 the retina provides a potential noninvasive window for early diagnosis of AD. 17 – 23 Neuroinflammation is a common pathological feature in AD. 24 , 25 Mouse models of AD and postmortem biopsy of patients with AD reveal retinal glial activation comparable to the central nervous system (CNS) immunoreactivity.…”