The Eye As a Biomarker for Alzheimer's Disease (original) (raw)
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Frontiers in neurology, 2016
Alzheimer's disease (AD) is the most common form of dementia affecting the growing aging population today, with prevalence expected to rise over the next 35 years. Clinically, patients exhibit a progressive decline in cognition, memory, and social functioning due to deposition of amyloid β (Aβ) protein and intracellular hyperphosphorylated tau protein. These pathological hallmarks of AD are measured either through neuroimaging, cerebrospinal fluid analysis, or diagnosed post-mortem. Importantly, neuropathological progression occurs in the eye as well as the brain, and multiple visual changes have been noted in both human and animal models of AD. The eye offers itself as a transparent medium to cerebral pathology and has thus potentiated the development of ocular biomarkers for AD. The use of non-invasive screening, such as retinal imaging and visual testing, may enable earlier diagnosis in the clinical setting, minimizing invasive and expensive investigations. It also potentiall...
Ocular indicators of Alzheimer's: exploring disease in the retina
Acta neuropathologica, 2016
Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer's disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aβ deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aβ42/40 peptides, morphologicall...
Ocular Biomarkers of Alzheimer's Disease: The Role of Anterior Eye and Potential Future Directions
Investigative Opthalmology & Visual Science
Globally, Alzheimer's disease (AD) is a growing health and economic challenge that has no effective cure. Recent clinical trials indicate that preclinical treatment may be required but a routine screening tool for AD has been elusive. Hence, a simple, yet sensitive biomarker for preclinical AD, when the disease is most likely to be amenable to treatment, is lacking. Due to several features, the eye has been explored for this purpose and, among the ocular tissues, the retina has received the most attention. Currently, major works investigating the potential AD diagnosis by detecting amyloid-b (Ab) signatures in the retinal tissue are underway, while the anterior eye is more accessible for in vivo imaging and examination. This report provides a concise review of current literature on the anterior eye components, including the crystalline lens, cornea, and aqueous humor, in AD. We also discuss the potential for assessment of the corneal nerve structure and regeneration as well as conjunctival tissue for AD-related alterations. The crystalline lens has received considerable attention, but further research is required to confirm whether Ab accumulates in the lens and whether it mirrors brain neuropathologic changes, particularly in preclinical AD. The rich corneal neural network and conjunctival vasculature also merit exploration in future studies to shed light on their potential association with AD pathologic changes.
Diagnostic and prognostic potential of retinal biomarkers in early on-set Alzheimer`s disease
Current Alzheimer research, 2017
Accumulating evidence suggests that the eye can be used in the assessment of early on-set Alzheimer's disease (AD). The eye offers a natural window to the brain through the retina. The retina and brain share common developmental origins and patho-physiological origins and mechanisms, having been sequestered from it during early development, but retaining its connections with the brain via the optic nerve. Therefore, it is well understood that neurological abnormalities have a direct profound impact on the retina. Recent studies suggest an array of physiological and pathological changes in the retina in dementia and specifically in AD. There are also reports on imaging the two hallmark proteins of the disease, extracellular amyloid beta peptides and intracellular hyper phosphorylated tau protein, as a proxy to neuroimaging. In this review, we summarise retinal structural, functional and vascular changes reported to be associated with AD. We also review techniques employed to imag...
Cell death & disease, 2018
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10-15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the...
Alzheimer's & Dementia, 2020
The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid, absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and towards validation of AD risk biomarkers that could potentially be used as a first step in a multi-step screening process for AD risk detection.
Ocular Manifestations of Alzheimer’s Disease in Animal Models
International Journal of Alzheimer's Disease, 2012
Alzheimer's disease (AD) is the most common form of dementia, and the pathological changes of senile plaques (SPs) and neurofibrillary tangles (NFTs) in AD brains are well described. Clinically, a diagnosis remains a postmortem one, hampering both accurate and early diagnosis as well as research into potential new treatments. Visual deficits have long been noted in AD patients, and it is becoming increasingly apparent that histopathological changes already noted in the brain also occur in an extension of the brain; the retina. Due to the optically transparent nature of the eye, it is possible to image the retina at a cellular level noninvasively and thus potentially allow an earlier diagnosis as well as a way of monitoring progression and treatment effects. Transgenic animal models expressing amyloid precursor protein (APP) presenilin (PS) and tau mutations have been used successfully to recapitulate the pathological findings of AD in the brain. This paper will cover the ocular abnormalities that have been detected in these transgenic AD animal models.
Brain Pathology, 2014
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders, and are characterized by deposition of specific proteins in the brain. If similar abnormal protein deposits are present in the eye, it would facilitate noninvasive diagnosis and monitoring of disease progression. We therefore evaluated expression of proteins associated with AD and PD pathology in postmortem eyes and brains in a case-control study. Eyes from 11 cases of AD, 6 cases of PD or PD with dementia, and 6 age-matched controls were retrieved from the autopsy archives of The Johns Hopkins Hospital. Immunostains for β-amyloid, phospho-tau and α-synuclein and Congo red stains were performed in the same laboratory in both brains and eyes. No amyloid deposits or abnormal tau accumulations were detected in the lens, retina or other structures in the eyes of AD patients. Eyes also lacked definite Lewy bodies or Lewy neurites in either PD or AD cases. Patchy cytoplasmic α-synuclein positivity was seen in the retina of AD, PD and control cases, but did not correlate with the presence or extent of Lewy body pathology in the brain. Abnormal protein aggregations characteristic of AD and PD are thus not commonly present in the retinas or lens of affected patients when assayed using the same protocols as in the brain. This suggests that β-amyloid, phospho-tau and α-synuclein either do not deposit in the eye in a manner analogous to brain, or are present at lower levels or in different forms. Brain Pathology ISSN 1015-6305 25 Brain Pathology 24 (2014) 25-32