In Vivo Visualization of Amyloid Deposits in the Heart with <sup>11</sup>C-PIB and PET

Antoni, Gunnar; Lubberink, Mark; Estrada, Sergio; Axelsson, Jan; Carlson, Kristina; Lindsjö, Lars; Kero, Tanja; Långström, Bengt; Granstam, Sven-Olof; Rosengren, Sara; Vedin, Ola; Wassberg, Cecilia; Wikström, Gerhard; Westermark, Per; Sörensen, Jens

doi:10.2967/jnumed.111.102053

Cited by 217 publications

(133 citation statements)

References 24 publications

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“…A method, now in use, has been developed where PET is used as a noninvasive diagnostic tool for the visualization of Aβ-deposits in the brain and a wide range of PET-ligands have been developed for the diagnosis of AD, one of the most common is Pittsburgh compound B, (PiB). [51,[95][96][97][98] Our interest in PET-ligands started when it was shown that PiB, (See figure 10), also could visualize amyloid deposits in the heart [99], although there are no generally available PET-ligands for imaging of amyloid deposits in heart, pancreas, liver and kidney. LCOs however, have shown specificity for different types of protein aggregates such as aggregates in prion diseases, AD and systemic amyloidosis [24,54,100,101].…”

Section: Positron Emission Tomographymentioning

confidence: 99%

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Johansson

2015

Linköping Studies in Science and Technology. Dissertations

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Luminescent conjugated polymers (LCPs) and luminescent conjugated oligothiophenes (LCOs) can be used as molecular probes to study diseases associated with protein aggregation. The conventionally used dyes to study and detect protein aggregates, denoted amyloid, have been Congo red (CR) and Thioflavin T (ThT). In contrast to these amyloid ligands, LCOs offer the possibility to detect aggregated proteinaceous species occurring at earlier stages of amyloid formation as well as to distinguish different morphotypes of protein aggregates. The interaction between the LCOs and the protein deposits can be studied by fluorescence spectroscopy and microscopy both in vitro and ex vivo. In this thesis we report the development of multimodal asymmetric LCOs that can be utilized with two novel techniques, Surface Plasmon Resonance (SPR) and Positron Emission Tomography (PET), to study and visualize the interaction between LCO and amyloid fibrils in real time. With SPR, we have been able to determine binding affinities between LCO and amyloid, and with PET we have shown that radiolabelled LCOs might be used as a non-invasive method to study amyloid deposits in vivo. In addition, by alteration of the backbone (change of thiophene units), and of adding different side chain functionalities, we have shown that the properties of the amyloid ligands have a huge impact of the binding to different stages or forms of protein aggregates. By making asymmetrical LCOs, which can be attached to a surface, we also foresee a methodology that will offer the possibility to create a sensitive and selective detection method, and maybe lead to a lab-on-a-chip-application. VIII IX POPULÄRVETENSKAPLIG SAMMANFATTNINGTidigare arbete i Peter Nilssons forskargrupp har visat att luminiscenta konjugerade polymerer (LCPs) och luminiscenta konjugerade oligotiofener (LCOs) kan användas som molekylära prober för att studera sjukdomar associerade till protein aggregering. De konventionellt använda markörerna för att studera och detektera proteinaggregat, så kallad amyloid, är Kongorött (CR) och Thioflavin T (ThT). I kontrast till dessa konventionella markörer har Nilssons forskargrupp visat att LCOs, på grund av deras flexibla konjugerade struktur, och laddning kan upptäcka både tidigare stadier av proteinaggregat samt också skilja på olika typer av aggregat. När LCO interagerar med proteinaggregaten kan denna interaktion studeras med fluorescens mikroskopi både in vitro och ex vivo. Arbetet i den här avhandlingen beskriver utvecklingen av amyloidligander från polymera till osymmetriska material samt två nya tekniker för att studera interaktionen mellan LCO och amyloida fibrer i realtid, Surface Plasmon Resonance (SPR) och Positron Emission Tomography (PET). Med SPR har vi kunnat bestämma bindingsaffiniteter mellan LCO och amyloida fibrer, och med PET har vi visat att radioinmärkta LCOs kan användas som en icke-invasiv metod för att studera amyloid in vivo. Under min forskarutbildning har jag syntetiserat och karaktäriserat både symmetriska och osymmetr...

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Section: Positron Emission Tomographymentioning

confidence: 99%

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Johansson

2015

Linköping Studies in Science and Technology. Dissertations

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“…Whereas these tracers are formally indicated for neuroamyloid imaging for the diagnosis of Alzheimer's disease, studies have shown that several of these tracers were detected in the myocardium in patients with systemic amyloid and suspected cardiac involvement (43)(44)(45). To date, no studies were published investigating cardiac amyloid by simultaneous PET/MR.…”

Section: Amyloidosismentioning

confidence: 99%

Disease-specific cardiovascular positron emission tomography/magnetic resonance imaging: a brief review of the current literature

Lau

Zheng

2016

Quant. Imaging Med. Surg.

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infiltrative, inflammatory and hereditary heart diseases, myocarditis, vasculitis, and cardiac mass assessment.The purpose of this review is to provide an overview of the current understanding of cardiovascular PET/ MR clinical imaging, in a disease-specific manner, from a clinician's perspective. Potential limitations of simultaneous PET/MR, such as cost effectiveness, artifacts, contraindications, and radiation exposure, are briefly discussed.

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“…As a consequence, rules have changed in this new field; lack of selectivity does not disqualify a tracer. Binding of a brain Aß tracer on a totally different kind of protein in cardiac amyloidosis is not questioning its value as a biomarker of a selective pathophysiological feature; on the contrary, it is actually presented as another opportunity of use [8]. So, if competition with specific ligands and selectivity do not validate these "protein load" tracers, how do we ascertain that the signal they produce is representative of the pathological process scrutinized?…”

mentioning

confidence: 99%

PET imaging of garbage protein in Alzheimer’s disease: does it require reappraisal of brain PET analysis?

Goldman

2014

Eur J Nucl Med Mol Imaging

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Imaging is in line with this prioritization [1]. The article describes initial results obtained with a new marker of tau protein deposits in the brain, 18 F-THK523. Tau is involved in a pathophysiological process considered pivotal in Alzheimer's disease and other dementing conditions grouped under the tauopathy denomination. The development of tracers targeting tau deposition is at the forefront in the search for valid biomarkers of dementing conditions. This research field was opened with the invention of the "PiB compound", the PET tracer of beta-amyloid (Aß) deposits [2]. The various works now dedicated to tau protein detection raise a basic question: why do we need a marker of tau protein deposits since we now have access to multiple Aß tracers which are reported to be supreme diagnostic tools in AD? One reason is that Aß accumulation seems less directly related to neuronal death than the tau metabolic disturbances leading to the welldefined neurofibrillary degeneration. Also, the early enthusiasm generated by the Aß tracers has been attenuated by the remembrance of some basic facts established several decades ago. Among these facts are the well-established presence of Aß plaques in the brain of subjects in good cognitive health and the poor correspondence of Aß distribution with the cognitive manifestations of AD. Since the distribution of neurofibrillary degeneration is better correlated with the typology of cognitive deficits, tau might be a better choice in the search for valid AD biomarkers. The initial attraction for Aß PET tracers also declined after the deceiving results of clinical studies aiming at amyloid clearance from AD patients' brain. These results have questioned the simplistic reasoning that equates disappearance of a single pathological feature with therapeutic benefit [3]. New questions have, therefore, been formulated such as, for instance, whether available amyloid PET tracers inform us about amyloid species that are the actual toxic actors in the pathophysiological process. The plea for a refined development of AD biomarkers has fuelled the search for PET tracers directed to tau deposits. This new effort is further encouraged by very recent and preliminary evaluations of therapeutic monoclonal antibodies that might reduce tau-related neurodegeneration [4]. Indeed, such new anti-AD strategies will require tools to assess the evolution of tau deposits in vivo. Such new tau tracers have been recently described [5,6]. Data obtained with the [ 11 C] PBB3 PET tracer are particularly promising since the uptake distribution in AD patients and in a patient with a corticobasal syndrome -a classic non-AD tauopathy-paralleled the distribution of tau deposits in these disorders.The new category of tracers targeting large concentrations of amorphous protidic deposits raise validation issues that deserve some attention. Indeed, the early PET tracers belonged to two categories that cannot accommodate the new "protein load" tracers such as the Aß and tau tracers. They were derived either from substrat...

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In Vivo Visualization of Amyloid Deposits in the Heart with ¹¹C-PIB and PET

Cited by 217 publications

References 24 publications

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Disease-specific cardiovascular positron emission tomography/magnetic resonance imaging: a brief review of the current literature

PET imaging of garbage protein in Alzheimer’s disease: does it require reappraisal of brain PET analysis?

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In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET

Cited by 217 publications

References 24 publications

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Asymmetric Oligothiophenes : Chemical Evolution of Multimodal Amyloid Ligands

Disease-specific cardiovascular positron emission tomography/magnetic resonance imaging: a brief review of the current literature

PET imaging of garbage protein in Alzheimer’s disease: does it require reappraisal of brain PET analysis?

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In Vivo Visualization of Amyloid Deposits in the Heart with ¹¹C-PIB and PET