| 1. |
- Just, Mie Kristine, et al.
(författare)
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Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : FRONTIERS MEDIA SA. - 1663-4365 .- 1663-4365. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinsons disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation. Increasing data suggest the clinical heterogeneity seen in patients is explained by the presence of distinct asyn strains, which exhibit variable morphologies and pathological functions. Recently, asyn seed amplification assays (PMCA and RT-QuIC) and conformation-specific ligand assays have made promising progress in differentiating between synucleinopathies in prodromal and advanced disease stages. Importantly, the cellular environment is known to impact strain morphology. And, asyn aggregate pathology can propagate trans-synaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Here, we present our hypothesis that the changing cellular environments, an asyn seed may encounter during its brain-to-body or body-to-brain propagation, may influence the structure and thereby the function of the aggregate strains developing within the different cells. Additionally, we aim to review strain characteristics of the different synucleinopathies in clinical and preclinical studies. Future preclinical animal models of synucleinopathies should investigate if asyn strain morphology is altered during brain-to-body and body-to-brain spreading using these seeding amplification and conformation-specific assays. Such findings would greatly deepen our understanding of synucleinopathies and the potential link between strain and phenotypic variability, which may enable specific diagnosis of different synucleinopathies in the prodromal phase, creating a large therapeutic window with potential future applications in clinical trials and personalized therapeutics.
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| 2. |
- Sehlin, Dag, 1976-, et al.
(författare)
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Engineered antibodies : new possibilities for brain PET?
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 46:13, s. 2848-2858
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Forskningsöversikt (refereegranskat)abstract
- Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.
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| 3. |
- Tolbod, Lars P., et al.
(författare)
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Non-invasive quantification of tumor blood flow in prostate cancer using O-15-H2O PET/CT
- 2018
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Ingår i: American Journal of Nuclear Medicine and Molecular Imaging. - : E-CENTURY PUBLISHING CORP. - 2160-8407. ; 8:5, s. 292-302
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Tidskriftsartikel (refereegranskat)abstract
- Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. O-15-water PET is the noninvasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRl) and post-surgical histopathology Gleason Grade. Dynamic O-15-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K-1) and wash-out (k(2)) constants was calculated using a one-compartmental model. Results: Mean (range) s PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k(2) was 0.44 (0.007-1.2), and K-1 was 0.24 (0.07-0.55) mL,/mL/min. k(2) (BSIF)correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k(2) and K-1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for O-15-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.
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| 4. |
- Xiong, Mengfei
(författare)
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Visualising neurodegeneration in the living brain : Preclinical evaluation of PET radioligands
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- With an ageing population, the number of people suffering from Alzheimer’s disease (AD) and Parkinson’s disease (PD) escalates yearly. Pathological hallmarks of AD and PD include aggregated proteins and synaptic dysfunction. Developing imaging probes targeting specific pathological hallmarks is highly valuable in aiding early diagnosis and treatment assessment.The thesis focused on evaluating positron emission tomography (PET) imaging probes that can visualise different pathological changes in preclinical models of neurodegeneration. Ligands targeting synaptic vesicle protein 2A (SV2A), alpha-synuclein (αSyn), and amyloid-beta (Aβ) are investigated.In paper I, we compared synaptic density in transgenic AD and PD mouse models to their wild-type age-matched controls using SV2A PET. In the hippocampus, lower synaptic density was found in the PD mice compared to the control. In paper II, we continued using SV2A PET and studied synaptic density in ageing mice. Synaptic density remained steady for most of the lifespan but slightly decreased in old age. In paper III, we developed and evaluated five antibody-based PET radioligands targeting αSyn aggregates. By conjugating anti-αSyn antibodies with the transferrin receptor (TfR) binder 8D3, we increased antibody brain entry significantly. These bispecific antibodies displayed high specificity and selectivity to αSyn aggregates. The most promising candidate successfully imaged brain-deposited αSyn but was unable to detect endogenously expressed αSyn in PD mouse models. In light of this, further investigation of antibody brain entry, distribution, and elimination is needed. Thus, in paper IV, we used microdialysis to compare the brain pharmacokinetics of a bispecific antibody targeting TfR and Aβ and its regular monospecific version that only binds to Aβ. The bispecific antibody showed distinct pharmacokinetics and entered the brain more efficiently than the regular antibody. Lastly, in paper V, we studied the impact of anti-Aβ antibody treatment on amyloid PET. AD mice were short-term treated with anti-Aβ antibody mAb158 and underwent [11C]PiB ex vivo autoradiography. We found a trend indicating that the treatment reduced the [11C]PiB signal despite no reduction in total Aβ levels.Our results contribute to an increased understanding of PET radioligands imaging neurodegeneration. Furthermore, it provides valuable information for designing and developing new PET radioligands.
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