Jarmo Teuho

Combination of magnetic field and surface functionalization for reaching synergistic effects in cellular labeling by magnetic core–shell nanospheres

Aimed at utilizing high-magnetization nanospheres for magnetic field-enhanced cellular labeling, core-shell structured sandwich-like magnetic mesoporous silica nanospheres were developed. While the magnetite cluster core can provide a high magnetic response for overcoming Brownian motion in cell culture media, the layered silica shell facilitates an efficient fluorescent dye labeling. However, the problem of particle aggregation in cell media, which is strongly enhanced under a magnetic field, significantly impeded the uptake by cells, resulting in difficulties in the precise analysis of the degree of particle internalization by fluorescence-based techniques (flow cytometry and confocal microscopy). To overcome this, reflection-based assessment was employed. Further, emphasis was put on utilizing the unique role of surface-hyperbranched polyethylenimine (PEI) in efficient prevention of particle aggregation prior to cell internalization in the presence of an external magnetic field. The interparticle attraction forces originating from magnetic dipole-dipole interactions are hereby balanced by the steric and electrostatic repulsion forces provided by the PEI functionalization, which leads to dispersed nanospheres in cell culture media during the magnetic-field induced cell labeling. As a consequence, PEI functionalization and the presence of the magnetic field synergistically enhanced the efficiency of MRI-fluorescence dual-mode labeling for cellular tracking.

Modulation of the structural properties of mesoporous silica nanoparticles to enhance the T1-weighted MR imaging capability

In this study, we have investigated the contrast enhancement of Gd(iii) incorporated nanoparticle-based contrast agents (CA) by the modulation of the synthesis and structural parameters of the mesoporous silica nanoparticle (MSN) matrix. In the optimisation process, the structure of the MSN matrix, post-synthesis treatment protocols, as well as the source and incorporation routes of paramagnetic gadolinium centers were considered, with the aim to shorten the T1 weighted relaxation time. After preliminary evaluation of the prepared MSNs as nanoparticulate T1/positive contrast agents based on relaxivity, the structure of the MSN matrix was affirmed as the most decisive property to enhance the r1 relaxivity value, alongside the incorporation route of paramagnetic Gd(iii) centers. Based on these findings, the most promising Gd(iii) incorporated MSN-based CA candidate was further evaluated for its cytocompatibility and intensity enhancement by in vitro phantom MR-imaging of labeled cells. Furthermore, pre-labeled tumors grown on a chick embryo chorioallantoic membrane (CAM) were imaged as an in vivo model on a 3T clinical MRI scanner. Our findings show that the optimized MSN-based CA design enables proper access of water to Gd-centers in the selected MSN matrices, and simultaneously decreases the required amount of Gd(iii) content per mass when evaluated against the other MSNs. Consequently, the required Gd amount on a per-dose basis is significantly decreased with regard to clinically used Gd-based CAs for T1-weighted MR imaging.

Comparison of end-expiratory respiratory gating methods for PET/CT

Abstract Background. Respiratory motion in positron emission tomography/computed tomography (PET/CT) causes underestimation of standardized uptake value (SUV) and variation of lesion volume, while PET and CT attenuation correction (CTAC) mismatch may introduce artefacts. The aim was to compare end-expiratory gating methods of PET and CTAC. Material and methods. Three methods named the minimum-constant, slope-based and amplitude-median were developed and evaluated on gating efficiency. Method evaluation and optimization was performed on 23 simulated and 23 recorded signals from a mixed patient group. The optimized methods were applied in PET/CT imaging of seven patients, consisting of non-gated CTAC, whole-body PET and four-dimensional (4D) PET/CT. Gating efficiency was evaluated by preservation of the respiratory signal, PET-CTAC alignment, image noise and measurement of lesion SUV maximum (SUVmax), SUV mean (SUVmean) and volume. The methods were evaluated with non-gated PET and end-expiratory phase of five-bin phase-gated PET. End-expiratory gated 4D-CTAC and averaged CTAC were compared for attenuation correction of end-expiratory gated PET. Results. Mean fraction of data preserved was larger (23–34%) with end-expiratory gating compared to phase-gated PET. End-expiratory gating showed increased SUVmax (8.2–8.4 g/ml), SUVmean (5.7–5.8 g/ml) and decreased lesion volume (-11.3–16.8%) compared to non-gated PET (SUVmax 6.2 g/ml, SUVmean 4.7 g/ml) and phase-gated PET (SUVmax 8.0 g/ml, SUVmean 5.6 g/ml). Using averaged CTAC and end-expiratory 4D-CTAC produced similar results concerning SUVmax, with less than 5% difference. Additionally, CTAC-PET-mismatch was minimal when end-expiratory 4D-CTAC was used. Conclusion. End-expiratory gating in PET/CT results in SUVmax and SUVmean increase and reduced lesion volume compared to non-gated PET and phase-gated PET. End-expiratory 4D-CTAC or averaged CTAC will offer similar accuracy for attenuation correction of end-expiratory gated PET.

Quantitative bias in PET/MR from attenuation correction and reconstruction: A comparison with PET and PET/CT with an anatomical brain phantom and Hoffman brain phantom

A comparison between PET/MR, PET/CT and PET was performed, to measure the bias due to attenuation coefficient assignment along with the effect of modifying the parameters in blob-RAMLA reconstruction algorithm. The measurements were performed by using an anatomical brain phantom with realistic head contour (Iida phantom) and a Hoffman brain phantom. The Iida phantom models the attenuation of the skull and uptake in the gray matter, with compartments for K2HPO4 solution and [F18]-FDG. The analysis consisted of comparison of 10 anatomical VOI regions and ratio images. Three blob parameters to maintain quantitative accuracy with improved image quality were evaluated. The error from misalignment and a location-specific bias was measured, for estimating the effect of attenuation. Additionally, attenuation correction was studied by comparing clinical MRAC with calculated MRAC derived from MR and measured attenuation maps derived from CTAC images. Modifying the blob parameters did not affect significantly to regional values on either of the phantoms; differences of 1-3 % in magnitude were measured. A misalignment of 2.53 mm was detected, producing asymmetry between hemispheres from 5 % to 19 %. After alignment correction, a location-specific bias ranging from 5 % to 17 % remained. The bias was reduced by taking into account the phantom skull either from calculated or measured attenuation correction; calculated attenuation introduced more bias. Selection of the RAMLA parameters accordingly did not affect quantification of the images. To improve the quantitative accuracy of the PET/MR systems, accurate tissue classification, attenuation coefficient assignment and alignment between PET and MRAC need to be accounted for. For testing and development of PET/MR instrumentation methods, novel phantoms fully compatible with PET/MR are needed.

Brain amyloid load and its associations with cognition and vascular risk factors in FINGER study

Objective To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors. Methods A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain 11C-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low-density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score. Results Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE ε4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups. Conclusions The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE ε4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET.

Effect of Attenuation Correction on Regional Quantification Between PET/MR and PET/CT: A Multicenter Study Using a 3-Dimensional Brain Phantom

A spatial bias in brain PET/MR exists compared with PET/CT, because of MR-based attenuation correction. We performed an evaluation among 4 institutions, 3 PET/MR systems, and 4 PET/CT systems using an anthropomorphic brain phantom, hypothesizing that the spatial bias would be minimized with CT-based attenuation correction (CTAC). Methods: The evaluation protocol was similar to the quantification of changes in neurologic PET studies. Regional analysis was conducted on 8 anatomic volumes of interest (VOIs) in gray matter on count-normalized, resolution-matched, coregistered data. On PET/MR systems, CTAC was applied as the reference method for attenuation correction. Results: With CTAC, visual and quantitative differences between PET/MR and PET/CT systems were minimized. Intersystem variation between institutions was +3.42% to −3.29% in all VOIs for PET/CT and +2.15% to −4.50% in all VOIs for PET/MR. PET/MR systems differed by +2.34% to −2.21%, +2.04% to −2.08%, and −1.77% to −5.37% when compared with a PET/CT system at each institution, and these differences were not significant (P ≥ 0.05). Conclusion: Visual and quantitative differences between PET/MR and PET/CT systems can be minimized by an accurate and standardized method of attenuation correction. If a method similar to CTAC can be implemented for brain PET/MRI, there is no reason why PET/MR should not perform as well as PET/CT.

Image quantification in high-resolution PET assessed with a new anthropomorphic brain phantom

Choice of the PET scanner and image reconstruction parameters have significant impact in quantitative positron-emission tomography (PET). Hoffman phantom is probably the most widely used test object for assessing this impact in brain PET studies. In high-resolution PET, however, its usability is questionable due to lesser partial-volume effect. Futhermore, Hoffman phantom is cylindrical and does not offer realistic attenuation effect for the skull. In the current work we used a novel brain phantom that was produced using a 3D-printer, and provides realistic head contour and skull attenuation effect. We scanned the phantom with latest generation whole-body PET/MR (Philips Ingenuity TF) and PET/CT (GE Discovery 690) scanners and in a brain dedicated high-resolution scanner (Siemens HRRT) to evaluate its usability for intra- and inter-scanner comparisons with regard to PET brain imaging. In all scanners reconstruction algorithm choice and number of iterations had significant impact on anatomical gray matter ROI values. As compared to the HRRT, whole-body scanners showed 3% to 15% (Philips Ingenuity TF) and 0% to 5% (GE D690) negative biases in gray matter ROIs, when iterative reconstruction with high number of iterations but without resolution modeling was used. Whereas, low number of iterations in Philips Ingenuity yielded negative biases of 7% to 19%, but inclusion of resolution modeling in GE D690 yielded 19% to 7% higher values. In the HRRT count statistics related negative bias of up to 6% was seen, when iterative reconstruction without resolution modeling was used. We conclude that the new three-dimensional brain phantom is suitable for assessing the impact of reconstruction parameters both within and between scanners. However, the lack of ground truth values hampers the interpretation of the results, and furthermore, the small differences we saw between whole-body and brain-dedicated scanners might be due to limited resolution of the 3D-printing.

Effects of meal and incretins in the regulation of splanchnic blood flow

Objective Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions. Design A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed. Methods Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with 15O-water and 15O-carbon monoxide, respectively. Results Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1. Conclusion Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow.

Bariatric Surgery Enhances Splanchnic Vascular Responses in Patients with Type 2 Diabetes

Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixed meal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion.

Tissue Probability-Based Attenuation Correction for Brain PET/MR by Using SPM8

Bone attenuation remains a methodological challenge in hybrid PET/MR, as bone is hard to visualize via magnetic resonance imaging (MRI). Therefore, novel methods for taking into account bone attenuation in MR-based attenuation correction (MRAC) are needed. In this study, we propose a tissue-probability based attenuation correction (TPB-AC), which employs the commonly available neurological toolbox SPM8, to derive a subject-specific μ-map by segmentation of T1-weighted MR images. The procedures to derive a μ-map representing soft tissue, air and bone from the New Segment function in SPM8 and MATLAB are described. Visual and quantitative comparisons against CT-based attenuation correction (CTAC) data were performed using two μ-values ( 0.135 cm-1 and 0.145 cm-1) for bone. Results show improvement of visual quality and quantitative accuracy of positron emission tomography (PET) images when TPB-AC μ-map is used in PET/MR image reconstruction. Underestimation in PET images was decreased by an average of 5 ±2 percent in the whole brain across all patients. In addition, the method performed well when compared to CTAC, with maximum differences (mean ± standard deviation) of - 3 ±2 percent and 2 ±4 percent in two regions out of 28. Finally, the method is simple and computationally efficient, offering a promising platform for further development. Therefore, a subject-specific MR-based μ-map can be derived only from the tissue probability maps from the New Segment function of SPM8.