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

Abstract

Introduction The retina and brain exhibit similar pathologies in patients diagnosed with neurodegenerative diseases. The ability to access the retina through imaging techniques opens the possibility for non‐invasive evaluation of Alzheimer's disease (AD) pathology. While retinal amyloid deposits are detected in individuals clinically diagnosed with AD, studies including preclinical individuals are lacking, limiting assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection. Methods In this small cross‐sectional study we compare retinal and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from a small subset of participants from both studies to determine retinal amyloid deposition at baseline. Results The four participants from the A4 trial showed a greater number of retinal spots compared to the four participants from the LEARN study. We observed a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr). Discussion The results of this small pilot study support the use of retinal fundus imaging for detecting amyloid deposition that is correlated with brain amyloid PET SUVr. A larger sample size will be necessary to fully ascertain the relationship between amyloid PET and retinal amyloid both cross‐sectionally and longitudinally.

No difference in retinal fluorescence after oral curcumin intake in amyloid‐proven AD cases compared to controls

“… 4 , 5 , 6 More specifically related to AD pathology, three small studies reported visualization of retinal amyloid beta (Aβ) deposits in vivo using curcumin, a polypotent polyphenol with fluorescent properties that binds to amyloid in post‐mortem brain tissue. 7 , 8 , 9 The presence of retinal amyloid beta deposits is, not unequivocally proven, however, since we and other groups could not confirm amyloid beta deposits in post‐mortem retinal tissue. 10 , 11 , 12 , 13 , 14 Moreover, curcumin is known for its low bioavailability, and although several commercially available formulations enhancing curcumin plasma levels are on the market, so far only one formulation (Longvida) has been reported to visualize retinal amyloid.…”

“…Three previous studies showed hyperfluorescence in AD cases after curcumin intake. 7 , 8 , 9 Although these studies were of similar small sample size, AD biomarker confirmation was lacking, which is essential when relating retinal changes to AD, since other structures may cause changes in fluorescence as well. For example, retinal drusen, associated with macular degeneration, contains amyloid and other age‐related deposits.…”

Microglia: Key Players in Retinal Ageing and Neurodegeneration

“…Aβ deposits in the retina have the potential to be a targeted biomarker for early AD diagnosis and disease progression. The natural compound curcumin binds to Aβ with a high degree of specificity and thus, retinal imaging of fluorescent curcumin has been explored in AD clinical trials and shown promising results ( Koronyo et al, 2017 ; Dumitrascu et al, 2020 ; Ngolab et al, 2021 ). A positive correlation between retinal curcumin-positive spots and brain amyloid has been observed in patients, suggesting that retinal curcumin imaging holds potential for the detection of preclinical AD and the progression of dementia ( Ngolab et al, 2021 ).…”

“…The natural compound curcumin binds to Aβ with a high degree of specificity and thus, retinal imaging of fluorescent curcumin has been explored in AD clinical trials and shown promising results ( Koronyo et al, 2017 ; Dumitrascu et al, 2020 ; Ngolab et al, 2021 ). A positive correlation between retinal curcumin-positive spots and brain amyloid has been observed in patients, suggesting that retinal curcumin imaging holds potential for the detection of preclinical AD and the progression of dementia ( Ngolab et al, 2021 ). Regarding the treatment and clearance of amyloid deposits, a recent study has co-cultured brain slices from aged AD mice with young WT mice and has shown that the phagocytic ability of aged microglia can be restored through factors secreted from young microglia, resulting in increased amyloid plaque clearance.…”

Label-Free Hyperspectral Imaging and Deep-Learning Prediction of Retinal Amyloid β-Protein and Phosphorylated Tau

“…[5–7,15,20–28] However, administrating contrast agents in humans complicates the imaging procedure, hindering its scalability for population screening. To date, only curcumin, a natural fluorochrome, has been tested and used in clinical trials to label retinal Aβ, [6,21–23,25] whereas fluorophores used to visualize retinal pTau in vivo are more limited. Therefore, there is an unmet need to develop label-free, high-resolution imaging techniques to visualize retinal Aβ and pTau deposits for early AD screening and disease management.…”