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Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 22798

Special Issue Editors

Prof. Dr. Ikuo Toyama

E-Mail Website
Guest Editor
Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
Interests: Alzheimer’s disease; biomarker; imaging probes for F19-MRI
Dr. Wellington Pham

E-Mail Website
Guest Editor
Department of Radiology and Radiological Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA
Interests: medicinal chemistry; biomarker imaging for opitical; PET and MRI

Special Issue Information

Dear Colleagues,

As we are progressing deeper into the 21st century, a bright sign is that people live longer thanks to the affordability of modern healthcare. However, as longevity improves, there are also, unfortunately, more incidences of dementia. Alzheimer’s Disease (AD) is the most common cause of dementia among elderly people. Currently, AD affects more than 30 million people worldwide. The mechanism that regulates neuronal degeneration in AD remains unknown; however, the definitive cytopathologic hallmarks of AD appear to be the formation and aggregation of amyloid plaques and intracellular hyperphosphorylated tau tangles, which together lead to profound neuronal toxicity. Currently, the clinical diagnosis of AD focuses on early deficits in memory, which typifies AD, but this phenotypical change is associated with the late stage of the disease, making treatment more challenging. With the asymptomatic characteristics of the disease, exacerbated by the variabilities’ onset, it is of paramount importance to find suitable AD biomarkers, not only for diagnosis and prognosis of the disease, but also for monitoring the response during therapy.

Altogether, this Special Issue will provide up-to-date information regarding the multifaceted research progress in AD. Although the amyloid-cascade hypothesis is central to many research works, nevertheless, the possibility of other contributing mechanisms in AD is also discussed to reflect the notion that AD is a difficult and complex disease. This issue’s collective research articles covering different aspects of AD research ranging from molecular biology to biomarker imaging and the innovative chemical development of molecular probes will offer valuable insights into the progress and the implications of these advanced technologies in AD research.

Prof. Dr. Ikuo Toyama
Assoc. Prof. Dr. Wellington Pham
Guest Editors

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Keywords

  • Amyloid beta
  • Tau phosphorylation
  • Retinal Abeta
  • Biomaker
  • Promethazine PET probe
  • F19-MRI probe

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Published Papers (6 papers)

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Research

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24 pages, 2447 KiB  
Article
Pilot Quality-Assurance Study of a Third-Generation Batch-Mode Clinical-Scale Automated Xenon-129 Hyperpolarizer
by Jonathan R. Birchall, Md Raduanul H. Chowdhury, Panayiotis Nikolaou, Yuri A. Chekmenev, Anton Shcherbakov, Michael J. Barlow, Boyd M. Goodson and Eduard Y. Chekmenev
Molecules 2022, 27(4), 1327; https://doi.org/10.3390/molecules27041327 - 16 Feb 2022
Cited by 5 | Viewed by 2915
Abstract
We present a pilot quality assurance (QA) study of a clinical-scale, automated, third-generation (GEN-3) 129Xe hyperpolarizer employing batch-mode spin-exchange optical pumping (SEOP) with high-Xe densities (50% natural abundance Xe and 50% N2 in ~2.6 atm total pressure sourced from Nova Gas [...] Read more.
We present a pilot quality assurance (QA) study of a clinical-scale, automated, third-generation (GEN-3) 129Xe hyperpolarizer employing batch-mode spin-exchange optical pumping (SEOP) with high-Xe densities (50% natural abundance Xe and 50% N2 in ~2.6 atm total pressure sourced from Nova Gas Technologies) and rapid temperature ramping enabled by an aluminum heating jacket surrounding the 0.5 L SEOP cell. 129Xe hyperpolarization was performed over the course of 700 gas loading cycles of the SEOP cell, simulating long-term hyperpolarized contrast agent production in a clinical lung imaging setting. High levels of 129Xe polarization (avg. %PXe = 51.0% with standard deviation σPXe = 3.0%) were recorded with fast 129Xe polarization build-up time constants (avg. Tb = 25.1 min with standard deviation σTb = 3.1 min) across the first 500 SEOP cell refills, using moderate temperatures of 75 °C. These results demonstrate a more than 2-fold increase in build-up rate relative to previously demonstrated results in a comparable QA study on a second-generation (GEN-2) 129Xe hyperpolarizer device, with only a minor reduction in maximum achievable %PXe and with greater consistency over a larger number of SEOP cell refill processes at a similar polarization lifetime duration (avg. T1 = 82.4 min, standard deviation σT1 = 10.8 min). Additionally, the effects of varying SEOP jacket temperatures, distribution of Rb metal, and preparation and operation of the fluid path are quantified in the context of device installation, performance optimization and maintenance to consistently produce high 129Xe polarization values, build-up rates (Tb as low as 6 min) and lifetimes over the course of a typical high-throughput 129Xe polarization SEOP cell life cycle. The results presented further demonstrate the significant potential for hyperpolarized 129Xe contrast agent in imaging and bio-sensing applications on a clinical scale. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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9 pages, 922 KiB  
Communication
A Fluorine-19 Magnetic Resonance Probe, Shiga-Y5, Downregulates Thioredoxin-Interacting Protein Expression in the Brain of a Mouse Model of Alzheimer’s Disease
by Aslina Pahrudin Arrozi, Zulzikry Hafiz Abu Bakar, Hiroyasu Taguchi, Daijiro Yanagisawa and Ikuo Tooyama
Molecules 2021, 26(17), 5342; https://doi.org/10.3390/molecules26175342 - 2 Sep 2021
Cited by 1 | Viewed by 2304
Abstract
Thioredoxin-interacting protein (TXNIP) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (TXN). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-β deposition in the brain, previously [...] Read more.
Thioredoxin-interacting protein (TXNIP) is involved in multiple disease-associated functions related to oxidative stress, especially by inhibiting the anti-oxidant- and thiol-reducing activity of thioredoxin (TXN). Shiga-Y5 (SY5), a fluorine-19 magnetic resonance probe for detecting amyloid-β deposition in the brain, previously showed therapeutic effects in a mouse model of Alzheimer’s disease; however, the mechanism of action of SY5 remains unclear. SY5 passes the blood–brain barrier and then undergoes hydrolysis to produce a derivative, Shiga-Y6 (SY6), which is a TXNIP-negative regulator. Therefore, this study investigates the therapeutic role of SY5 as the prodrug of SY6 in the thioredoxin system in the brain of a mouse model of Alzheimer’s disease. The intraperitoneal injection of SY5 significantly inhibited TXNIP mRNA (p = 0.0072) and protein expression (p = 0.0143) induced in the brain of APP/PS1 mice. In contrast, the levels of TXN mRNA (p = 0.0285) and protein (p = 0.0039) in the brain of APP/PS1 mice were increased after the injection of SY5. The ratio of TXN to TXNIP, which was decreased (p = 0.0131) in the brain of APP/PS1 mice, was significantly increased (p = 0.0072) after the injection of SY5. These results suggest that SY5 acts as a prodrug of SY6 in targeting the thioredoxin system and could be a potential therapeutic compound in oxidative stress-related diseases in the brain. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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11 pages, 979 KiB  
Article
Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography
by Clayton A. Whitmore, Mariam I. Boules, William J. Behof, Justin R. Haynes, Dmitry Koktysh, Adam J. Rosenberg, Mohammed N. Tantawy and Wellington Pham
Molecules 2021, 26(8), 2182; https://doi.org/10.3390/molecules26082182 - 10 Apr 2021
Cited by 1 | Viewed by 3840
Abstract
Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer’s disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this [...] Read more.
Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer’s disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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11 pages, 7642 KiB  
Article
Fluorine-19 Magnetic Resonance Imaging for Detection of Amyloid β Oligomers Using a Keto Form of Curcumin Derivative in a Mouse Model of Alzheimer’s Disease
by Daijiro Yanagisawa, Nor Faeizah Ibrahim, Hiroyasu Taguchi, Shigehiro Morikawa, Takami Tomiyama and Ikuo Tooyama
Molecules 2021, 26(5), 1362; https://doi.org/10.3390/molecules26051362 - 4 Mar 2021
Cited by 12 | Viewed by 2703
Abstract
Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer’s disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in [...] Read more.
Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer’s disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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12 pages, 2427 KiB  
Article
Inhalable Thioflavin S for the Detection of Amyloid Beta Deposits in the Retina
by Shawn M. Barton, Eleanor To, Baxter P. Rogers, Clayton Whitmore, Manjosh Uppal, Joanne A. Matsubara and Wellington Pham
Molecules 2021, 26(4), 835; https://doi.org/10.3390/molecules26040835 - 5 Feb 2021
Cited by 11 | Viewed by 4417
Abstract
We present an integrated delivery technology herein employing the aerosolized method to repurpose thioflavin S for imaging amyloid beta (Abeta) deposits in the retina as a surrogate of Abeta in the brain for early detection of Alzheimer’s disease. The data showed that wild [...] Read more.
We present an integrated delivery technology herein employing the aerosolized method to repurpose thioflavin S for imaging amyloid beta (Abeta) deposits in the retina as a surrogate of Abeta in the brain for early detection of Alzheimer’s disease. The data showed that wild type (WT) mice also have Abeta deposits in the retinae, albeit much less than 5XFAD mice. Further, only in 5XFAD mice, significant Abeta deposits were found associated with retinal ganglion cells (RGCs) in whole-mount and cross-section data. Furthermore, the fluorescent signal depicted from thioflavin S corroborates with Abeta immunohistochemistry staining information. Overall, this probe delivery via inhalation method is also applicable to other Abeta-binding molecules, such as Congo red, curcumin, and thioflavin T. The advantage of imaging retinal amyloid deposits compared to the brain counterparts is that the eye is easily accessible by in vivo imaging and it reduces the effort to design a probe that must cross the formidable blood-brain barrier. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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Review

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29 pages, 2084 KiB  
Review
Nicotinic Acetylcholine Receptors and Microglia as Therapeutic and Imaging Targets in Alzheimer’s Disease
by Kazuyuki Takata, Hiroyuki Kimura, Daijiro Yanagisawa, Koki Harada, Kaneyasu Nishimura, Yoshihisa Kitamura, Shun Shimohama and Ikuo Tooyama
Molecules 2022, 27(9), 2780; https://doi.org/10.3390/molecules27092780 - 27 Apr 2022
Cited by 15 | Viewed by 5621
Abstract
Amyloid-β (Aβ) accumulation and tauopathy are considered the pathological hallmarks of Alzheimer’s disease (AD), but attenuation in choline signaling, including decreased nicotinic acetylcholine receptors (nAChRs), is evident in the early phase of AD. Currently, there are no drugs that can suppress the progression [...] Read more.
Amyloid-β (Aβ) accumulation and tauopathy are considered the pathological hallmarks of Alzheimer’s disease (AD), but attenuation in choline signaling, including decreased nicotinic acetylcholine receptors (nAChRs), is evident in the early phase of AD. Currently, there are no drugs that can suppress the progression of AD due to a limited understanding of AD pathophysiology. For this, diagnostic methods that can assess disease progression non-invasively before the onset of AD symptoms are essential, and it would be valuable to incorporate the concept of neurotheranostics, which simultaneously enables diagnosis and treatment. The neuroprotective pathways activated by nAChRs are attractive targets as these receptors may regulate microglial-mediated neuroinflammation. Microglia exhibit both pro- and anti-inflammatory functions that could be modulated to mitigate AD pathogenesis. Currently, single-cell analysis is identifying microglial subpopulations that may have specific functions in different stages of AD pathologies. Thus, the ability to image nAChRs and microglia in AD according to the stage of the disease in the living brain may lead to the development of new diagnostic and therapeutic methods. In this review, we summarize and discuss the recent findings on the nAChRs and microglia, as well as their methods for live imaging in the context of diagnosis, prophylaxis, and therapy for AD. Full article
(This article belongs to the Special Issue Innovative Molecular Probes and Imaging Technology for the Detection of Alzheimer’s Disease and Dementia-Related Disorders)
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