Detection of Amyloid β Signature in the Lens and Its Correlation in the Brain to Aid in the Diagnosis of Alzheimer’s Disease

Kerbage, C.; Sadowsky, Carl; Tariot, Pierre N.; Agronin, Marc E.; Alva, Gustavo; Turner, F.; Nilan, Dennis; Cameron, A.; Cagle, Gerald D.; Hartung, P.

doi:10.1177/1533317513520214

Cited by 42 publications

(44 citation statements)

References 29 publications

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“…On the other hand, a study employing the standard staining protocols for brain tissues, was unable to detect aggregates of Aβ, pTau, or α-synuclein upon examination of retinal cross sections and other ocular tissues from AD and Parkinson’s disease (PD) patients [82]. It is important to note, however, that studies from eight independent groups examining eyes from AD patients have consistently found retinal tauopathy and increased formation of Aβ deposits in retinas and lenses [1, 69, 101, 102, 107, 113, 133, 163, 178], and two recent studies examining retinas from patients with PD or Tg mice modeling PD and Dementia with Lewy Bodies reported the presence of misfolded α-synuclein within the inner retinal layers, along with impaired vision [23, 155]. …”

Section: Hallmark Pathology In Ocular Tissues Of Ad Patientsmentioning

confidence: 99%

Ocular indicators of Alzheimer’s: exploring disease in the retina

et al. 2016

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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, morphologically diverse Aβ plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aβ deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.

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Section: Hallmark Pathology In Ocular Tissues Of Ad Patientsmentioning

confidence: 99%

Ocular indicators of Alzheimer’s: exploring disease in the retina

et al. 2016

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“…44–47 Ocular Aβ imaging could obviate the need for expensive and short-lived radiolabeled probes and PET imaging equipment, instead relying on relatively inexpensive retinal or lens fluorescence imagers. 44–48 Further reducing the complexity of the diagnostic procedure, ocular amyloid detection probes can be orally ingested or topically applied.…”

Section: Resultsmentioning

confidence: 99%

“…44–48 Further reducing the complexity of the diagnostic procedure, ocular amyloid detection probes can be orally ingested or topically applied. 46, 47 In contrast to promiscuous curcumin-based fluorescent probes, 49 novel fluorescent clicked PiB derivatives have the potential for significantly higher affinity and selectivity towards Aβ in vivo . Therefore, fluorescent clicked PiB derivatives could also provide a viable alternative to more hazardous radioactivity-based PiB PET imaging studies.…”

Section: Resultsmentioning

confidence: 99%

Generation of Clickable Pittsburgh Compound B for the Detection and Capture of β-Amyloid in Alzheimer’s Disease Brain

et al. 2017

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The benzothiazole-aniline derivative Pittsburgh Compound B (PiB) is the prototypical amyloid affinity probe developed for the in vivo positron emission tomography (PET) detection of amyloid beta (Aβ) deposits in Alzheimer’s disease (AD). Specific high-affinity binding sites for PiB have been found to vary among AD cases with comparable Aβ load, and they are virtually absent on human-sequence Aβ deposits in animal models, none of which develop the full phenotype of AD. PiB thus could be an informative probe for studying the pathobiology of Aβ, but little is known about the localization of PiB binding at the molecular or structural level. By functionalizing the 6-hydroxy position of PiB with a PEG3 spacer and a terminal alkyne (propargyl) moiety, we have developed a clickable PiB compound that was derivatized with commercially available azide-labeled fluorophores or affinity-tags using copper-catalyzed azide-alkyne cycloaddition reactions, commonly referred to as “click” chemistry. We have determined that both the clickable PiB derivative and its fluorescently-labeled conjugate have low nanomolar binding affinities for synthetic Aβ aggregates. Furthermore, the fluorescent-PiB conjugate can effectively bind Aβ aggregates in human AD brain homogenates and tissue sections. By covalently coupling PiB to magnetic beads, Aβ aggregates were also affinity-captured from AD brain extracts. Thus, the clickable PiB derivative described herein can be used to generate a wide variety of covalent conjugates, with applications including the fluorescence detection of Aβ, the ultrastructural localization of PiB binding, and the affinity capture and structural characterization of Aβ and other co-factors from AD brains.

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“…They determined that Ab specific frequency counts in the AD group were more than 2-fold higher than those of the control group. In their subsequent, relatively larger study using the fluorescent ligand eye scanning (FLES) technique in the crystalline lens, 24 the same research team reported capability of the technique to discriminate a group of people with probable AD (n ¼ 20) from healthy controls (n ¼ 20). In their examiner-masked, age-matched case control cohort, a sensitivity and specificity of 85% and 95%, respectively, was obtained for diagnosis of AD.…”

Section: The Crystalline Lensmentioning

confidence: 99%

“…23 The lens also has shown promise as a potential site for the presence of Ab signature in AD. 24,25 However, the remaining anterior eye structures have received less attention compared to the posterior segment. Although exploring AD-specific alterations in the retina is worthwhile and the outcomes are encouraging, capturing quality images suitable for analysis is limited by several factors, including pupil size, formation of senile cataracts, and media opacities.…”

mentioning

confidence: 99%