Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost, Shaun; Martins, Ralph N.; Kanagasingam, Yogesan

doi:10.3233/jad-2010-100819

Cited by 100 publications

(82 citation statements)

References 152 publications

(184 reference statements)

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“…As retinal and cerebral microvasculature share many morphological and physiological properties (34), these vascular amyloid findings may explain the well-documented narrowing of venous blood column diameter and reduced blood flow in both the retinas (19,20,33,76,92) and brains (93)(94)(95) of AD patients. Recently, a mechanism for such phenomena was proposed in a study using murine models of AD demonstrating that vascular amyloid could harden blood vessel walls and decrease blood flow (96).…”

Section: Discussionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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BACKGROUND. Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS.Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS.Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ 42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION.The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

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Section: Discussionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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“…In light of the current lack of reliable early AD diagnosis and limitations in biomarker detection, AD-related changes in the retina may provide a unique opportunity for noninvasive imaging of A ␤ plaque burden with a high degree of detail and accuracy [25,51,52] . The retina is a central nervous system tissue, originating as an outgrowth of the developing brain.…”

Section: The Retina: a Window To View Ad?mentioning

confidence: 99%

Alzheimer’s Disease in the Retina: Imaging Retinal Aβ Plaques for Early Diagnosis and Therapy Assessment

et al. 2012

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Background: Definite Alzheimer’s disease (AD) diagnosis at early stages is vital for targeting intervention, yet currently unavailable. Noninvasive detection of the pathological hallmark, amyloid-β protein (Aβ) plaques, is limited in the brain. However, the existence of Aβ plaques in the retina, possibly at presymptomatic stages, may improve early detection of AD. Objective: To summarize clinical and preclinical evidence showing that the retina, an accessible part of the central nervous system, displays abnormalities in AD, especially Aβ plaque pathology. The ability to monitor in vivo retinal plaque dynamics in response to immunotherapy is also assessed. Methods: Literature analysis of retinal AD pathology and imaging is provided. In our studies, systemic curcumin is administered to enable monitoring of retinal Aβ plaques in live APP_SWE/PS1_Δ_E9 transgenic mice by optical imaging. Results: Visual and retinal abnormalities, including early manifestation of retinal Aβ plaque pathology, have been documented in AD patients and animal models. In mouse models, retinal Aβ plaques accumulate with age and decrease in response to immunotherapy, consistent with brain pathology. Here, we demonstrate that retinal plaques can be individually monitored in real time following glatiramer acetate immunization. Conclusion: Translation of noninvasive retinal-plaque imaging to humans could eventually facilitate early and accurate AD diagnosis and therapy assessment.

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“…[27][28][29][30] A great variety and quantity of biomarkers related to eyes 31 or spinal fluid 32 can be found. Specifically for the eyes, hypersensitivity in pupil response to acetylcholine 33 or tropicamide, 34 amyloid beta (AB) protein deposits in the crystalline 35 or the aqueous and vitreous humour region, 36 and a flow reduction of the retina venules measured with echo-Doppler 37 have been proposed as biomarkers of the cognitive impairment.…”

Section: Discussionmentioning

confidence: 99%

Macular Thickness in Subjective Memory Complaints and Mild Cognitive Impairment: A Non-Invasive Biomarker

Castejón

Dudekova

Gallego

et al. 2016

Neuro-Ophthalmology

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Alzheimer's disease (AD) is the main cause of dementia worldwide, which implies an important socioeconomic problem in developed countries. Efforts to find biomarkers to diagnose AD have been intensified, especially, to detect cognitive impairment in its early stages, also known as mild cognitive impairment (MCI). Besides, there are individuals referring memory loss that is unnoticeable in the family environment and presenting normal neuropsychological tests. The former patients are included in a clinical picture that has been recently called subjective memory complaints (SMC). To achieve an early diagnosis, optical coherence tomography (OCT) has been used to measure macular thickness in patients diagnosed with MCI (supported by neuropsychological tests) and SMC (not based on neuropsychological battery). Statistically significant differences have been found in the macular thickness of the control group (274.96 ± 17.61 µm) and for both MCI (259.48 ± 22.39 µm) and SMC (261.45 ± 24.26 µm) patients. In the near future, OCT could become a reliable biomarker and a useful tool for AD screening as well as for the monitoring of the cognitive impairment associated with AD. ARTICLE HISTORY

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Ocular Biomarkers for Early Detection of Alzheimer's Disease

Cited by 100 publications

References 152 publications

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Alzheimer’s Disease in the Retina: Imaging Retinal Aβ Plaques for Early Diagnosis and Therapy Assessment

Macular Thickness in Subjective Memory Complaints and Mild Cognitive Impairment: A Non-Invasive Biomarker

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