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Biomolecules
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Novel Imaging Biomarkers for Brain PET Imaging
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Novel Imaging Biomarkers for Brain PET Imaging

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biomarkers".

Deadline for manuscript submissions: closed (15 July 2023) | Viewed by 18944

Special Issue Editors

Dr. Anne M. Landau

E-Mail Website1 Website2
Guest Editor
1. Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
2. Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark
Interests: positron emission tomography (PET); neurodegenerative disorders; putative therapeutics
Special Issues, Collections and Topics in MDPI journals
Dr. Francisco R. Lopez-Picon

E-Mail Website
Guest Editor
PET Preclinical imaging Unit, University of Turku, Turku, ‎Finland
Interests: positron emission tomography; animal models; Alzheimer´s disease; neuroinflammation; schizophrenia
Dr. Nadja Van Camp

E-Mail Website
Guest Editor
Université Paris-Saclay, CEA, CNRS, MIRCen, Laboratoire des Maladies Neurodégénératives, Fontenay-aux-Roses, France
Interests: positron emission tomography; animal models; neuroinflammation; Parkinson’s disease

Special Issue Information

Dear Colleagues,

Neuroimaging using positron emission tomography (PET) has provided unique insights into brain function in living individuals under normal and diseased states. While initial studies focused on spatial brain activation patterns and glucose metabolism, the development of countless PET radioligands has provided access to the imaging of brain receptors, transporters, and enzymes with high selectivity and specificity. As such, PET allows for a successful estimation of neurotransmitter systems, neuroinflammation, synaptic density, and protein aggregation both in humans and in animal models. The possibility to image subjects has repeatedly offered PET a prominent role in clinical diagnosis, longitudinal monitoring of disease progression, and in drug development studies evaluating pharmacokinetics, target engagement, or dose occupancy.

Considering the growing understanding of neuropathophysiology, we believe it is timely to initiate a research topic on the advances in novel PET neuroimaging biomarkers and to highlight the need for novel targets. In this Special Issue, we welcome manuscripts (original papers, opinions, and reviews) on in vivo PET and/or postmortem autoradiography evaluation and validation of novel radioligands in animal models; on human PET imaging studies using novel radioligands; on innovative PET imaging approaches; and on the description and proposition of novel targets for radioligand development for brain imaging.

Dr. Anne Landau
Dr. Francisco R. Lopez-Picon
Dr. Nadja Van Camp
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • positron emission tomography
  • neuroscience
  • drug development
  • neurology
  • biomarkers

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Published Papers (7 papers)

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Research

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10 pages, 456 KiB  
Article
EEG Frequency Correlates with α2-Receptor Density in Parkinson’s Disease
by Adam F. Kemp, Martin Kinnerup, Birger Johnsen, Steen Jakobsen, Adjmal Nahimi and Albert Gjedde
Biomolecules 2024, 14(2), 209; https://doi.org/10.3390/biom14020209 - 10 Feb 2024
Viewed by 1423
Abstract
Introduction: Increased theta and delta power and decreased alpha and beta power, measured with quantitative electroencephalography (EEG), have been demonstrated to have utility for predicting the development of dementia in patients with Parkinson’s disease (PD). Noradrenaline modulates cortical activity and optimizes cognitive processes. [...] Read more.
Introduction: Increased theta and delta power and decreased alpha and beta power, measured with quantitative electroencephalography (EEG), have been demonstrated to have utility for predicting the development of dementia in patients with Parkinson’s disease (PD). Noradrenaline modulates cortical activity and optimizes cognitive processes. We claim that the loss of noradrenaline may explain cognitive impairment and the pathological slowing of EEG waves. Here, we test the relationship between the number of noradrenergic α2 adrenoceptors and changes in the spectral EEG ratio in patients with PD. Methods: We included nineteen patients with PD and thirteen healthy control (HC) subjects in the study. We used positron emission tomography (PET) with [11C]yohimbine to quantify α2 adrenoceptor density. We used EEG power in the delta (δ, 1.5–3.9 Hz), theta (θ, 4–7.9 Hz), alpha (α, 8–12.9 Hz) and beta (β, 13–30 Hz) bands in regression analyses to test the relationships between α2 adrenoceptor density and EEG band power. Results: PD patients had higher power in the theta and delta bands compared to the HC volunteers. Patients’ theta band power was inversely correlated with α2 adrenoceptor density in the frontal cortex. In the HC subjects, age was correlated with, and occipital background rhythm frequency (BRF) was inversely correlated with, α2 adrenoceptor density in the frontal cortex, while occipital BRF was inversely correlated with α2 adrenoceptor density in the thalamus. Conclusions: The findings support the claim that the loss or dysfunction of noradrenergic neurotransmission may relate to the parallel processes of cognitive decline and EEG slowing. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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12 pages, 1008 KiB  
Article
Distribution of α2-Adrenergic Receptors in the Living Human Brain Using [11C]yohimbine PET
by Chloé Laurencin, Sophie Lancelot, Inès Merida, Nicolas Costes, Jérôme Redouté, Didier Le Bars, Philippe Boulinguez and Bénédicte Ballanger
Biomolecules 2023, 13(5), 843; https://doi.org/10.3390/biom13050843 - 15 May 2023
Cited by 3 | Viewed by 1872
Abstract
The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [11C]yohimbine in a large sample [...] Read more.
The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [11C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20–50) to perform direct quantification of regional alpha 2 adrenergic receptors’ (α2-ARs) availability in the living human brain. The global map shows the highest [11C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [11C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α2-ARs is suspected. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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21 pages, 5187 KiB  
Article
[18F]GE-180-PET and Post Mortem Marker Characteristics of Long-Term High-Fat-Diet-Induced Chronic Neuroinflammation in Mice
by Luisa Müller, Nicole Power Guerra, Anna Schildt, Tobias Lindner, Jan Stenzel, Newshan Behrangi, Carina Bergner, Teresa Alberts, Daniel Bühler, Jens Kurth, Bernd Joachim Krause, Deborah Janowitz, Stefan Teipel, Brigitte Vollmar and Angela Kuhla
Biomolecules 2023, 13(5), 769; https://doi.org/10.3390/biom13050769 - 28 Apr 2023
Cited by 2 | Viewed by 2065
Abstract
Obesity is characterized by immoderate fat accumulation leading to an elevated risk of neurodegenerative disorders, along with a host of metabolic disturbances. Chronic neuroinflammation is a main factor linking obesity and the propensity for neurodegenerative disorders. To determine the cerebrometabolic effects of diet-induced [...] Read more.
Obesity is characterized by immoderate fat accumulation leading to an elevated risk of neurodegenerative disorders, along with a host of metabolic disturbances. Chronic neuroinflammation is a main factor linking obesity and the propensity for neurodegenerative disorders. To determine the cerebrometabolic effects of diet-induced obesity (DIO) in female mice fed a long-term (24 weeks) high-fat diet (HFD, 60% fat) compared to a group on a control diet (CD, 20% fat), we used in vivo PET imaging with the radiotracer [18F]FDG as a marker for brain glucose metabolism. In addition, we determined the effects of DIO on cerebral neuroinflammation using translocator protein 18 kDa (TSPO)-sensitive PET imaging with [18F]GE-180. Finally, we performed complementary post mortem histological and biochemical analyses of TSPO and further microglial (Iba1, TMEM119) and astroglial (GFAP) markers as well as cerebral expression analyses of cytokines (e.g., Interleukin (IL)-1β). We showed the development of a peripheral DIO phenotype, characterized by increased body weight, visceral fat, free triglycerides and leptin in plasma, as well as increased fasted blood glucose levels. Furthermore, we found obesity-associated hypermetabolic changes in brain glucose metabolism in the HFD group. Our main findings with respect to neuroinflammation were that neither [18F]GE-180 PET nor histological analyses of brain samples seem fit to detect the predicted cerebral inflammation response, despite clear evidence of perturbed brain metabolism along with elevated IL-1β expression. These results could be interpreted as a metabolically activated state in brain-resident immune cells due to a long-term HFD. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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16 pages, 2417 KiB  
Article
Combined In Vivo Microdialysis and PET Studies to Validate [11C]Yohimbine Binding as a Marker of Noradrenaline Release
by Anne Marlene Landau, Steen Jakobsen, Majken Borup Thomsen, Aage Kristian Olsen Alstrup, Dariusz Orlowski, Jan Jacobsen, Gregers Wegener, Arne Mørk, Jens Christian Hedemann Sørensen and Doris J. Doudet
Biomolecules 2023, 13(4), 674; https://doi.org/10.3390/biom13040674 - 14 Apr 2023
Cited by 1 | Viewed by 1981
Abstract
The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore [...] Read more.
The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [11C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [11C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [11C]yohimbine volumes of distribution (VT) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine VT, with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine VT. These data suggest that [11C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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Review

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36 pages, 2140 KiB  
Review
The Sensitivity of Tau Tracers for the Discrimination of Alzheimer’s Disease Patients and Healthy Controls by PET
by Zohreh Mohammadi, Hadi Alizadeh, János Marton and Paul Cumming
Biomolecules 2023, 13(2), 290; https://doi.org/10.3390/biom13020290 - 3 Feb 2023
Cited by 11 | Viewed by 3054
Abstract
Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer’s disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, [...] Read more.
Hyperphosphorylated tau aggregates, also known as neurofibrillary tangles, are a hallmark neuropathological feature of Alzheimer’s disease (AD). Molecular imaging of tau by positron emission tomography (PET) began with the development of [18F]FDDNP, an amyloid β tracer with off-target binding to tau, which obtained regional specificity through the differing distributions of amyloid β and tau in AD brains. A concerted search for more selective and affine tau PET tracers yielded compounds belonging to at least eight structural categories; 18F-flortaucipir, known variously as [18F]-T807, AV-1451, and Tauvid®, emerged as the first tau tracer approved by the American Food and Drug Administration. The various tau tracers differ concerning their selectivity over amyloid β, off-target binding at sites such as monoamine oxidase and neuromelanin, and degree of uptake in white matter. While there have been many reviews of molecular imaging of tau in AD and other conditions, there has been no systematic comparison of the fitness of the various tracers for discriminating between AD patient and healthy control (HC) groups. In this narrative review, we endeavored to compare the binding properties of the various tau tracers in vitro and the effect size (Cohen’s d) for the contrast by PET between AD patients and age-matched HC groups. The available tracers all gave good discrimination, with Cohen’s d generally in the range of two–three in culprit brain regions. Overall, Cohen’s d was higher for AD patient groups with more severe illness. Second-generation tracers, while superior concerning off-target binding, do not have conspicuously higher sensitivity for the discrimination of AD and HC groups. We suppose that available pharmacophores may have converged on a maximal affinity for tau fibrils, which may limit the specific signal imparted in PET studies. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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16 pages, 1124 KiB  
Review
ImmunoPET Directed to the Brain: A New Tool for Preclinical and Clinical Neuroscience
by Ángel García de Lucas, Urpo Lamminmäki and Francisco R. López-Picón
Biomolecules 2023, 13(1), 164; https://doi.org/10.3390/biom13010164 - 13 Jan 2023
Cited by 3 | Viewed by 4973
Abstract
Immuno-positron emission tomography (immunoPET) is a non-invasive in vivo imaging method based on tracking and quantifying radiolabeled monoclonal antibodies (mAbs) and other related molecules, such as antibody fragments, nanobodies, or affibodies. However, the success of immunoPET in neuroimaging is limited because intact antibodies [...] Read more.
Immuno-positron emission tomography (immunoPET) is a non-invasive in vivo imaging method based on tracking and quantifying radiolabeled monoclonal antibodies (mAbs) and other related molecules, such as antibody fragments, nanobodies, or affibodies. However, the success of immunoPET in neuroimaging is limited because intact antibodies cannot penetrate the blood–brain barrier (BBB). In neuro-oncology, immunoPET has been successfully applied to brain tumors because of the compromised BBB. Different strategies, such as changes in antibody properties, use of physiological mechanisms in the BBB, or induced changes to BBB permeability, have been developed to deliver antibodies to the brain. These approaches have recently started to be applied in preclinical central nervous system PET studies. Therefore, immunoPET could be a new approach for developing more specific PET probes directed to different brain targets. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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Other

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22 pages, 3130 KiB  
Perspective
Peering into the Brain’s Estrogen Receptors: PET Tracers for Visualization of Nuclear and Extranuclear Estrogen Receptors in Brain Disorders
by Shokouh Arjmand, Dirk Bender, Steen Jakobsen, Gregers Wegener and Anne M. Landau
Biomolecules 2023, 13(9), 1405; https://doi.org/10.3390/biom13091405 - 18 Sep 2023
Viewed by 2224
Abstract
Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs’ intricate landscape has shown promise in oncology but remains limited in the [...] Read more.
Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs’ intricate landscape has shown promise in oncology but remains limited in the context of brain disorders. Despite recent progress in the identification and development of more selective ligands for various ERs subtypes, further optimization is necessary to enable the reliable and efficient imaging of these receptors. In this perspective, we briefly touch upon the significance of estrogen signaling in the brain and raise the setbacks associated with the development of PET tracers for identification of specific ERs subtypes in the brain. We then propose avenues for developing efficient PET tracers to non-invasively study the dynamics of ERs in the brain, as well as neuropsychiatric diseases associated with their malfunction in a longitudinal manner. This perspective puts several potential candidates on the table and highlights the unmet needs and areas requiring further research to unlock the full potential of PET tracers for ERs imaging, ultimately aiding in deepening our understanding of ERs and forging new avenues for potential therapeutic strategies. Full article
(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)
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