Advances in ophthalmic imaging research on retinal biomarkers of Alzheimer's disease_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Luyao , He Hailong ,  Jin Zibing

Beijing Tongren Hospital, Capital Medical University, Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, National Engineering Research Center for Ophthalmology, Beijing 100730, China;

Corresponding author：

Jin Zibing, Email: jinzb502@ccmu.edu.cn

Keywords：

Alzheimer’s disease; Ophthalmic imaging; Retina; Biomarker; Review

DOI：

10.3760/cma.j.cn511434-20250603-00239

Video：

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Abstract Full text Figures/Tables Video References Cited by

Alzheimer's disease (AD) is a neurodegenerative disorder with insidious onset and poor prognosis, and it is the primary cause of senile dementia. Its early diagnosis is challenging, and existing methods mostly rely on high-cost and invasive examinations. As an integral part of the central nervous system, the retina provides a non-invasive and efficient observation window for AD diagnosis. In recent years, with the development of ophthalmic imaging technologies such as optical coherence tomography, optical coherence tomography angiography, and hyperspectral imaging, a growing number of studies have revealed that AD patients exhibit retinal structural changes, structural and functional abnormalities of retinal blood vessels, and that amyloid-beta and Tau deposits can be detected via specific imaging methods—suggesting that these changes may occur prior to brain lesions. Meanwhile, the integrated analysis of multimodal imaging shows promising prospects in identifying retinal biomarkers and predicting AD risk, demonstrates the significant potential of retinal imaging technology in the early screening, diagnosis, and disease progression monitoring of AD, and provides a new source of biomarkers and potential clinical applications for AD research.

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1. 张丽, 李建桥. 重视全身疾病的眼部表现[J]. 眼科学报, 2023, 38(5): 365-370. DOI: 10.12419/j.issn.1000-4432.2023.05.01.Zhang L, Li JQ. Attach importance to ocular manifestations of systemic diseases[J]. Eye Science, 2023, 38(5): 365-370. DOI: 10.12419/j.issn.1000-4432.2023.05.01.
2. Gustavsson A, Norton N, Fast T, et al. Global estimates on the number of persons across the Alzheimer's disease continuum[J]. Alzheimers Dement, 2023, 19(2): 658-670. DOI: 10.1002/alz.12694.
3. Feke GT, Hyman BT, Stern RA, et al. Retinal blood flow in mild cognitive impairment and Alzheimer's disease[J]. Alzheimers Dement (Amst), 2015, 1(2): 144-151. DOI: 10.1016/j.dadm.2015.01.004.
4. Huang Q, Cohen MA, Alsina FC, et al. Intravital imaging of mouse embryos[J]. Science, 2020, 368(6487): 181-186. DOI: 10.1126/science.aba0210.
5. Jiang X, Xie M, Ma L, et al. International publication trends in the application of artificial intelligence in ophthalmology research: an updated bibliometric analysis[J/OL]. Ann Transl Med, 2023, 11(5): 219[2023-03-09]. https://pubmed.ncbi.nlm.nih.gov/37007552/. DOI: 10.21037/atm-22-3773.
6. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years[J]. EMBO Mol Med, 2016, 8(6): 595-608. DOI: 10.15252/emmm.201606210.
7. Chan VTT, Ran AR, Wagner SK, et al. Value proposition of retinal imaging in Alzheimer's disease screening: a review of eight evolving trends[J/OL]. Prog Retin Eye Res, 2024, 103: 101290[2024-08-22]. https://pubmed.ncbi.nlm.nih.gov/39173942/. DOI: 10.1016/j.preteyeres.2024.101290.
8. Masland RH. The fundamental plan of the retina[J]. Nat Neurosci, 2001, 4(9): 877-886. DOI: 10.1038/nn0901-877.
9. Ge YJ, Xu W, Ou YN, et al. Retinal biomarkers in Alzheimer's disease and mild cognitive impairment: a systematic review and meta-analysis[J/OL]. Ageing Res Rev, 2021, 69: 101361[2021-05-14]. https://pubmed.ncbi.nlm.nih.gov/34000463/. DOI: 10.1016/j.arr.2021.101361.
10. Cheung CY, Ong YT, Ikram MK, et al. Microvascular network alterations in the retina of patients with Alzheimer's disease[J]. Alzheimers Dement, 2014, 10(2): 135-142. DOI: 10.1016/j.jalz.2013.06.009.
11. Grimaldi A, Pediconi N, Oieni F, et al. Neuroinflammatory processes, A1 astrocyte activation and protein aggregation in the retina of Alzheimer's disease patients, possible biomarkers for early diagnosis[J/OL]. Front Neurosci, 2019, 13: 925[2019-09-04]. https://pubmed.ncbi.nlm.nih.gov/31551688/. DOI: 10.3389/fnins.2019.00925.
12. Georgevsky D, Retsas S, Raoufi N, et al. A longitudinal assessment of retinal function and structure in the APP/PS1 transgenic mouse model of Alzheimer's disease[J/OL]. Transl Neurodegener, 2019, 8: 30[2019-10-01]. https://pubmed.ncbi.nlm.nih.gov/31592131/. DOI: 10.1186/s40035-019-0170-z.
13. Ho WL, Leung Y, Cheng SS, et al. Investigating degeneration of the retina in young and aged tau P301L mice[J]. Life Sci, 2015, 124: 16-23. DOI: 10.1016/j.lfs.2014.12.019.
14. 延艳妮, 魏文斌, 汪东生. 眼科光学相干断层扫描技术的新进展[J]. 中华眼科医学杂志 (电子版), 2013, 2(1): 38-40. DOI: 10.3877/cma.j.issn.2095-2007.2013.01.012.Yan YN, Wei WB, Wang DS. New development of optical coherence tomography in ophtalmology[J]. Chin J Ophthalmol (Electronic Edition), 2013, 2(1): 38-40. DOI: 10.3877/cma.j.issn.2095-2007.2013.01.012.
15. Choi SH, Park SJ, Kim NR. Macular ganglion cell -inner plexiform layer thickness is associated with clinical progression in mild cognitive impairment and Alzheimers disease[J/OL]. PLoS One, 2016, 11(9): e0162202[2016-09-06]. https://pubmed.ncbi.nlm.nih.gov/27598262/. DOI: 10.1371/journal.pone.0162202.
16. Sheriff S, Shen T, Abdal S, et al. Retinal thickness and vascular parameters using optical coherence tomography in Alzheimer's disease: a meta-analysis[J]. Neural Regen Res, 2023, 18(11): 2504-2513. DOI: 10.4103/1673-5374.371380.
17. Carazo-Barrios L, Archidona-Arranz A, Claros-Ruiz A, et al. Correlation between retinal nerve fibre layer thickness and white matter lesions in Alzheimer's disease[J]. Int J Geriatr Psychiatry, 2021, 36(6): 935-942. DOI: 10.1002/gps.5496.
18. Mathew S, Wudunn D, Mackay DD, et al. Association of brain volume and retinal thickness in the early stages of Alzheimer's disease[J]. J Alzheimers Dis, 2023, 91(2): 743-752. DOI: 10.3233/JAD-210533.
19. Lian TH, Jin Z, Qu YZ, et al. The relationship between retinal nerve fiber layer thickness and clinical symptoms of Alzheimer's disease[J/OL]. Front Aging Neurosci, 2020, 12: 584244[2021-01-29]. https://pubmed.ncbi.nlm.nih.gov/33584241/. DOI: 10.3389/fnagi.2020.584244.
20. Kim JI, Kang BH. Decreased retinal thickness in patients with Alzheimer's disease is correlated with disease severity[J/OL]. PLoS One, 2019, 14(11): e0224180[2019-11-15]. https://pubmed.ncbi.nlm.nih.gov/31689310/. DOI: 10.1371/journal.pone.0224180.
21. Mutlu U, Colijn JM, Ikram MA, et al. Association of retinal neurodegeneration on optical coherence tomography with dementia: a population-based study[J]. JAMA Neurol, 2018, 75(10): 1256-1263. DOI: 10.1001/jamaneurol.2018.1563.
22. Álvarez-Rodríguez L, Pueyo A, de Moura J, et al. Fully automatic deep convolutional approaches for the screening of neurodegeneratives diseases using multi-view OCT images[J/OL]. Artif Intell Med, 2024, 158: 103006[2024-11-01]. https://pubmed.ncbi.nlm.nih.gov/39504622/. DOI: 10.1016/j.artmed.2024.103006.
23. Lee MW, Park KS, Lim HB, et al. Long-term reproducibility of GC-IPL thickness measurements using spectral domain optical coherence tomography in eyes with high myopia[J/OL]. Sci Rep, 2018, 8(1): 11037[2018-07-23]. https://pubmed.ncbi.nlm.nih.gov/30038425/. DOI: 10.1038/s41598-018-29466-8.
24. Cheung CY, Ong YT, Hilal S, et al. Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer's disease[J]. J Alzheimers Dis, 2015, 45(1): 45-56. DOI: 10.3233/JAD-141659.
25. Van Der Heide FCT, Steens ILM, Limmen B, et al. Thinner inner retinal layers are associated with lower cognitive performance, lower brain volume, and altered white matter network structure-The Maastricht Study[J]. Alzheimers Dement, 2024, 20(1): 316-329. DOI: 10.1002/alz.13442.
26. Wisely CE, Wang D, Henao R, et al. Convolutional neural network to identify symptomatic Alzheimer's disease using multimodal retinal imaging[J]. Br J Ophthalmol, 2022, 106(3): 388-395. DOI: 10.1136/bjophthalmol-2020-317659.
27. Frost S, Kanagasingam Y, Sohrabi H, et al. Retinal vascular biomarkers for early detection and monitoring of Alzheimer's disease[J/OL]. Transl Psychiatry, 2013, 3(2): e233[2013-02-26]. https://pubmed.ncbi.nlm.nih.gov/23443359/. DOI: 10.1038/tp.2012.150.
28. Golzan M, Goozee K, Georgevsky D, et al. Retinal vascular and structural changes are associated with amyloid burden in the elderly: ophthalmic biomarkers of preclinical Alzheimer's disease[J/OL]. Alzheimers Res Ther, 2017, 9(1): 13[2017-03-01]. https://pubmed.ncbi.nlm.nih.gov/28253913/. DOI: 10.1186/s13195-017-0239-9.
29. Olafsdottir OB, Saevarsdottir HS, Hardarson SH, et al. Retinal oxygen metabolism in patients with mild cognitive impairment[J]. Alzheimers Dement (Amst), 2018, 10: 340-345. DOI: 10.1016/j.dadm.2018.03.002.
30. Cheung C Y, Ran A R, Wang S, et al. A deep learning model for detection of Alzheimer's disease based on retinal photographs: a retrospective, multicentre case-control study[J/OL]. Lancet Digit Health, 2022, 4(11): e806-e815[2022-09-30]. https://pubmed.ncbi.nlm.nih.gov/36192349/. DOI: 10.1016/S2589-7500(22)00169-8.
31. Pead E, Thompson AC, Grewal DS, et al. Retinal vascular changes in Alzheimer's dementia and mild cognitive impairment: a pilot study using ultra-widefield imaging[J/OL]. Transl Vis Sci Technol, 2023, 12(1): 13[2023-01-03]. https://pubmed.ncbi.nlm.nih.gov/36622689/. DOI: 10.1167/tvst.12.1.13.
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