Association of Early Beta-amyloid Accumulation and Neuroinflammation Measured with [11C]PBR28 in Elderly Individuals Without Dementia

OBJECTIVE: To examine whether early β-amyloid (Aβ) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0, 56% women, 51% APOE ε4 carriers) with a TSPO-tracer [11C]PBR28 to assess neuroinflammation and with [11C]Pittsburgh compound B (PiB) to assess cerebral Aβ accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in six regions of interests by using the cerebellar cortex as a pseudo-reference/reference region, respectively. Fasting venous glucose, insulin, and high sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n=11) underwent CSF sampling, and Aβ40, Aβ42, total-tau, phospho-tau, soluble TREM2 and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p=0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid negative ([11C]PiB composite score ≤1.5) (TSPO-genotype, age and sex adjusted slope 0.26, p=0.008) but not among amyloid positive participants (slope: -0.004, p=0.88). Higher CSF sTREM2 (rs 0.72, p=0.01) and YKL-40 (rs=0.63, p=0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aβ accumulation is first detected in Alzheimer's disease (AD). CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology

Folate receptor-targeted positron emission tomography of experimental autoimmune encephalomyelitis in rats

AbstractBACKGROUND: Folate receptor-β (FR-β) is a cell surface receptor that is significantly upregulated on activated macrophages during inflammation and provides a potential target for folate-based therapeutic and diagnostic agents. FR-β expression in central nervous system inflammation remains relatively unexplored. Therefore, we used focally induced acute and chronic phases of experimental autoimmune encephalomyelitis (EAE) to study patterns of FR-β expression and evaluated its potential as an in vivo imaging target. METHODS: Focal EAE was induced in rats using heat-killed Bacillus Calmette-Guérin followed by activation with complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. The rats were assessed with magnetic resonance imaging and positron emission tomography/computed tomography (PET/CT) at acute (14 days) and chronic (90 days) phases of inflammation. The animals were finally sacrificed for ex vivo autoradiography of their brains. PET studies were performed using FR-β-targeting aluminum [18F]fluoride-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate ([18F]AlF-NOTA-folate, 18F-FOL) and 18 kDa translocator protein (TSPO)-targeting N-acetyl-N-(2-[11C]methoxybenzyl)-2-phenoxy-5-pyridinamine (11C-PBR28). Post-mortem immunohistochemistry was performed using anti-FR-β, anti-cluster of differentiation 68 (anti-CD68), anti-inducible nitric oxide synthase (anti-iNOS), and anti-mannose receptor C-type 1 (anti-MRC-1) antibodies. The specificity of 18F-FOL binding was verified using in vitro brain sections with folate glucosamine used as a blocking agent. RESULTS: Immunohistochemical evaluation of focal EAE lesions demonstrated anti-FR-β positive cells at the lesion border in both acute and chronic phases of inflammation. We found that anti-FR-β correlated with anti-CD68 and anti-MRC-1 immunohistochemistry; for MRC-1, the correlation was most prominent in the chronic phase of inflammation. Both 18F-FOL and 11C-PBR28 radiotracers bound to the EAE lesions. Autoradiography studies verified that this binding took place in areas of anti-FR-β positivity. A blocking assay using folate glucosamine further verified the tracer's specificity. In the chronic phase of EAE, the lesion-to-background ratio of 18F-FOL was significantly higher than that of 11C-PBR28 (P = 0.016). CONCLUSION: Our EAE results imply that FR-β may be a useful target for in vivo imaging of multiple sclerosis-related immunopathology. FR-β-targeted PET imaging with 18F-FOL may facilitate the monitoring of lesion development and complement the information obtained from TSPO imaging by bringing more specificity to the PET imaging armamentarium for neuroinflammation. </div

Radiosynthesis and preclinical evaluation of [68Ga]Ga-NOTA-folate for PET imaging of folate receptor β-positive macrophages

Folate receptor β (FR-β), a marker expressed on macrophages, is a promising target for imaging of inflammation. Here, we report the radiosynthesis and preclinical evaluation of [68Ga]Ga-NOTA-folate (68Ga-FOL). After determining the affinity of 68Ga-FOL using cells expressing FR-β, we studied atherosclerotic mice with 68Ga-FOL and 18F-FDG PET/CT. In addition, we studied tracer distribution and co-localization with macrophages in aorta cryosections using autoradiography, histology, and immunostaining. The specificity of 68Ga-FOL was assessed in a blocking study with folate glucosamine. As a final step, human radiation doses were extrapolated from rat PET data. We were able to produce 68Ga-FOL with high radiochemical purity and moderate molar activity. Cell binding studies revealed that 68Ga-FOL had 5.1 nM affinity for FR-β. Myocardial uptake of 68Ga-FOL was 20-fold lower than that of 18F-FDG. Autoradiography and immunohistochemistry of the aorta revealed that 68Ga-FOL radioactivity co-localized with Mac-3–positive macrophage-rich atherosclerotic plaques. The plaque-to-healthy vessel wall ratio of 68Ga-FOL was significantly higher than that of 18F-FDG. Blocking studies verified that 68Ga-FOL was specific for FR. Based on estimations from rat data, the human effective dose was 0.0105 mSv/MBq. Together, these findings show that 68Ga-FOL represents a promising new FR-β–targeted tracer for imaging macrophage-associated inflammation.</p

Fast growth associated with aberrant vasculature and hypoxia in fibroblast growth factor 8b (FGF8b) over-expressing PC-3 prostate tumour xenografts

Background: Prostate tumours are commonly poorly oxygenated which is associated with tumour progression and development of resistance to chemotherapeutic drugs and radiotherapy. Fibroblast growth factor 8b (FGF8b) is a mitogenic and angiogenic factor, which is expressed at an increased level in human prostate tumours and is associated with a poor prognosis. We studied the effect of FGF8b on tumour oxygenation and growth parameters in xenografts in comparison with vascular endothelial growth factor (VEGF)-expressing xenografts, representing another fast growing and angiogenic tumour model. Methods: Subcutaneous tumours of PC-3 cells transfected with FGF8b, VEGF or empty (mock) vectors were produced and studied for vascularity, cell proliferation, glucose metabolism and oxygenation. Tumours were evaluated by immunohistochemistry (IHC), flow cytometry, use of radiolabelled markers of energy metabolism ([F-18] FDG) and hypoxia ([F-18] EF5), and intratumoral polarographic measurements of pO(2). Results: Both FGF8b and VEGF tumours grew rapidly in nude mice and showed highly vascularised morphology. Perfusion studies, pO(2) measurements, [F-18] EF5 and [F-18] FDG uptake as well as IHC staining for glucose transport protein (GLUT1) and hypoxia inducible factor (HIF) 1 showed that VEGF xenografts were well-perfused and oxygenised, as expected, whereas FGF8b tumours were as hypoxic as mock tumours. These results suggest that FGF8b-induced tumour capillaries are defective. Nevertheless, the growth rate of hypoxic FGF8b tumours was highly increased, as that of well-oxygenised VEGF tumours, when compared with hypoxic mock tumour controls. Conclusion: FGF8b is able to induce fast growth in strongly hypoxic tumour microenvironment whereas VEGF-stimulated growth advantage is associated with improved perfusion and oxygenation of prostate tumour xenografts

Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography

Inflammation plays an important role in the development of atherosclerosis and its complications. Because the folate receptor beta (FR-beta) is selectively expressed on macrophages, an FR targeted imaging agent could be useful for assessment of atherosclerotic inflammation. We investigated aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate (F-18-FOL) for the detection of atherosclerotic plaque inflammation. We studied atherosclerotic plaques in mice, rabbits, and human tissue samples using F-18-FOL positron emission tomography/computed tomography (PET/CT). Compound 2-deoxy-2-[F-18]fluoro-D-glucose (F-1(8)-FDG) was used as a comparison. Firstly, we found that the in vitro binding of F-18-FOL co-localized with FR-beta-positive macrophages in carotid endarterectomy samples from patients with recent ischemic symptoms. We then demonstrated specific accumulation of intravenously administered F-18-FOL in atherosclerotic plaques in mice and rabbits using PET/CT. We noticed that the F-18-FOL uptake correlated with the density of macrophages in plaques and provided a target-to-background ratio as high as F-18-FDG, but with considerably lower myocardial uptake. Thus, F-18-FOL PET/CT targeting of FR-beta-positive macrophages presents a promising new tool for the in vivo imaging of atherosclerotic inflammation

Rediscovering vitamin D

Over the past 2 years there has been a radical change in standard clinical practice with respect to vitamin D. As a result of a growing body of knowledgeable physicians are assessing the vitamin D nutritional status of their patients and prescribing aggressive repletion regimens of a vitamin D supplement. The present paper summarizes some basic information about this essential nutrient and reviews some of the more recent data implicating vitamin D deficiency in disease etiology with an emphasis on cardiovascular disease and cancer. Finally a rational approach to the dosing of vitamin D in different patient populations is provided

Evolution and trends of business intelligence systems:a systematic mapping study

Business Intelligence or BI can be defined as an umbrella term describing a combination of applications, infrastructures, tools, processes, best practises and methods to gather, prepare, provide and analyse data to support decision making activities in organizations. BI is noted to have ties to preceding research on similar systems, known as MIS, DSS and EIS-systems. BI is noted to have been born after requirement to answer the challenges of data gathering and turning the data into knowledge for decision-making. Early BI-development can be seen to have be affected by the development and lowering in costs of technologies in data gathering, analysis, interactivity and personal computing, as well as the introduction of spreadsheet programs in 1980s. Today, BI is noted to be the top investment-area for IT-organizations. Because of multidimensional nature and several viewpoints, it can be challenging to gain an overall view of the area. It is also noted, that a standardized framework of the different BI-related layers or aspects does not exist. The goal of this thesis is to identify which aspects can be noted central for BI, how the area has developed over time, how technological innovation has affected BI and which industries or aspects are noticed to have influenced the development most. Systematic Mapping Study is used as the main research methodology in this thesis, together with PRISMA, which is used for a more scrutinized review during the selection process. The methods were used to review a large number of studies, gathered from academic databases using a formalized search string. The process provided with two sets of primary studies with total number of 2020 for studying the trends and central aspects in the area of BI and 1414 for studying the industries. From the results, BI is noted to have gained popularity early 2000s, peaking in 2012–2013, while fading coming to 2016. The results show the central aspects for BI from high-level to be: strategic aspects, data warehousing methods and BI-infrastructure. From more detail, the central aspects are noted to be strategic aspects, data warehousing, BI-design aspects, real-time functionalities, visualization features, decision support, collaborative support, reporting and cloud infrastructure. The major industries influencing BI-development and research is noted to be finance and banking, healthcare, supply chain, e-commerce, manufacturing and education. Today, most notable interest is noticed in Big Data. In future, Big Data, self-service, collaboration features, visualization, user aspects and mobility are predicted as some of the rising topics. BI is noted shifting more into non-profit organizations and extending the use-context. Major changes in the area are seen to be caused by IT-base innovation, while most changes in BI may be seen to be caused by services-innovation where new industries and methods are found to utilize BI-technology. BI is noted as a very strategic entity, consisting of data warehousing methods, different decision support methods and technologies. In the future, BI-technology will be spread into more widespread use and the lessons learnt might be valuable for the predicted revolution caused by Big Data analytics and extended data collection and analysis