The Retinal Inner Plexiform Synaptic Layer Mirrors Grey Matter Thickness of Primary Visual Cortex with Increased Amyloid β Load in Early Alzheimer’s Disease

Abstract

The retina may serve as putative window into neuropathology of synaptic loss in Alzheimer’s disease (AD). Here, we investigated synapse-rich layers versus layers composed by nuclei/cell bodies in an early stage of AD. In addition, we examined the associations between retinal changes and molecular and structural markers of cortical damage. We recruited 20 AD patients and 17 healthy controls (HC). Combining optical coherence tomography (OCT), magnetic resonance (MR), and positron emission tomography (PET) imaging, we measured retinal and primary visual cortex (V1) thicknesses, along with V1 amyloid β (Aβ) retention ([11C]-PiB PET tracer) and neuroinflammation ([11C]-PK11195 PET tracer). We found that V1 showed increased amyloid-binding potential, in the absence of neuroinflammation. Although thickness changes were still absent, we identified a positive association between the synapse-rich inner plexiform layer (IPL) and V1 in AD. This retinocortical interplay might reflect changes in synaptic function resulting from Aβ deposition, contributing to early visual loss.

Associations between thinner retinal neuronal layers and suboptimal brain structural integrity: Are the eyes a window to the brain?

“…An increasing number of studies have investigated whether retinal neuronal measurements are associated with brain measurements at various stages of AD. The findings are inconsistent, with some studies finding an association between retinal and brain measurements (Jorge et al, 2020; López-de-Eguileta et al, 2022; Mauschitz et al, 2022; Mejia-Vergara et al, 2021; Méndez-Gómez et al, 2018; Mutlu et al, 2018, 2017; Shi et al, 2020, 2019; Uchida et al, 2020), some finding no association (Casaletto et al, 2017; den Haan et al, 2019), and others with inconclusive results (Donix et al, 2021). However, methodological differences may explain some of this inconsistency—systematic differences between OCT or MRI devices across manufacturers and models, choice of parameters and settings, and the wide range of measurements which can be acquired from each of these technologies make comparison across studies difficult.…”

Feasibility study for detection of retinal amyloid in clinical trials: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial

“…We observed a modest correlation between brain PET SUVr and retinal spot count, suggesting a pathologically relevant relationship between the brain and the retina. While a recent study suggests a relationship between the primary visual cortex and the inner plexiform layer of the retina, 25 multiple regions of the neocortex were measured to calculate SUVr in this current study. Future retinal imaging study designs may consider measuring other brain regions associated with the retina, such as the lateral geniculate and primary visual cortex.…”

Inhalable Thioflavin S for the Detection of Amyloid Beta Deposits in the Retina

“…In particular, SPECT imaging is greatly improved by the integrated use of visual assessment and statistical analysis. Non-radioisotopic probes for imaging AD include [ 19 F] fluoride Congo red and [ 19 F] curcumin mimetics [11,12]; perfluoro agents, such as styrylbenzoxazole analogs have also emerged [12]. Among the tested compounds, the styrylbenzoxazole compound linked with seven ethylene glycol groups in the PEG (polyethylene glycol) chain showed significant [ 19 F]MR signals in the brains of AβPPswe/PS1dE9 mice compared to wild type (WT) counterparts.…”

“…An alternative to these limitations is afforded by the recent discovery of Abeta deposition in the retinae of humans diagnosed with AD [ 17 ], as well as in the retinae of preclinical mouse models [ 18 ]. In a clinical study, comparing the retinal functions of AD patients ( n = 20) versus healthy people ( n = 17) using PET, MRI, and optical coherence tomography (OCT), the work showed that the retinae are also found with increased Abeta load in early AD [ 19 ]. The proof-of-concept clinical imaging for the detection of Abeta in the retinae was explored recently using a commercially available curcumin-based Longvida probe [ 20 ].…”