Previous MRI studies reported cortical iron accumulation in early-onset (EOAD) compared to late-onset (LOAD) Alzheimer disease patients. However, the pattern and origin of iron accumulation is poorly understood. This study investigated the histopathological correlates of MRI contrast in both EOAD and LOAD. T2*-weighted MRI was performed on postmortem frontal cortex of controls, EOAD, and LOAD. Images were ordinally scored using predefined criteria followed by histology. Nonlinear histology-MRI registration was used to calculate pixel-wise spatial correlations based on the signal intensity. EOAD and LOAD were distinguishable based on 7T MRI from controls and from each other. Histology-MRI correlation analysis of the pixel intensities showed that the MRI contrast is best explained by increased iron accumulation and changes in cortical myelin, whereas amyloid and tau showed less spatial correspondence with T2*-weighted MRI. Neuropathologically, subtypes of Alzheimer's disease showed different patterns of iron accumulation and cortical myelin changes independent of amyloid and tau that may be detected by high-field susceptibility-based MRI.

Recently, debate has arisen about the usefulness of cell tracking using iron oxide-labeled cells. Two important issues in determining the usefulness of cell tracking with MRI are generally overlooked; first, the effect of graft rejection in immunocompetent models, and second, the necessity for careful histological confirmation of the fate of the labeled cells in the presence of iron oxide. Therefore, both iron oxide-labeled living as well as dead epicardium-derived cells (EPDCs) were investigated in ischemic myocardium of immunodeficient non-obese diabetic (NOD)/acid: non-obese diabetic severe combined immunodeficient (NOD/scid) mice with 9.4T MRI until 6 weeks after surgery, at which time immunohistochemical analysis was performed. In both groups, voids on MRI scans were observed that did not change in number, size, or localization over time. Several studies demonstrated that iron-labeled cellular transplants were visible with MRI and could be followed over time (3,4,6,7), even when a magnet of clinical field strength was used (4,8), although the detection limit was low and only high numbers of iron-loaded cells were visible (9). It was only assumed that these hypointense spots on the MRI images actually represented the transplanted living iron-loaded cells. It was not verified whether the transplanted cells were indeed present in histological sections, and whether MRI signal was really generated by the original transplant and not by, e.g., macrophages that had phagocytosed the iron-containing cells. The first study (5) that addressed this issue reported that the MRI signal originally generated by iron in transplanted MSCs appeared to be present regardless of the existence of these cells, which was later confirmed by Terrovitis et al. (10), who demonstrated, like Amsalem et al. (5) had done before, that iron-loaded macrophages created the signal rather than the iron-loaded living transplanted cells.As suggested by Sadek and Garry (11) in a comment on the study of Amsalem et al. (5), the results should be extended by studies in immunocompromised animals. In the previous studies, cardiac-derived stem cells (CDCs) or MSCs, which are not immunoprivileged, were harvested from "syngeneic" rats and transplanted into other inbred immunocompetent rats (5,10). However, rats cannot, unlike mouse donors from same inbred strain, be considered really syngeneic but rather allogeneic (5), implying that the cells could simply be rejected by the host, and thus that the concern regarding the utility of SPIOs in cardiac cell therapy applies only to comparable studies with nonautologous cells and immunocompetent animals. Sadek and Garry (11), therefore, pleaded for similar experiments with either autologous cell transplantation in normal animals, or with allogeneic stem cell transplantation into immunodeficient animals (11). It could very well be that iron-loaded transplanted cells are not rejected in those settings or that the clearance pattern is altered in such a way that the hypointense signals from iron-oxide largely correspon...

The value of iron-based MRI changes for the diagnosis and staging of Alzheimer’s disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2*-weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo.

Objective-In search of molecular imaging modalities for specific detection of inflammatory atherosclerotic plaques, we explored the potential of targeting scavenger receptor-AI (SR-AI), which is highly expressed by lesional macrophages and linked to effective internalization machinery. Approach and Results-Ultrasmall superparamagnetic iron oxide particles were conjugated to a peptidic SR-AI ligand (0.371 mol Fe/L and 0.018 mol PP1/L). In vitro incubation of human or murine macrophages with SR-AI-targeted USPIO led to significantly higher iron uptake in vitro than with nontargeted USPIO, as judged by quantitative atomic absorption spectroscopy and Perl's staining. Incremental uptake was strictly mediated by SRs. SR-AI-targeted USPIO displayed accelerated plasma decay and a 3.5-fold increase (P=0.01) in atherosclerotic plaque accumulation on intravenous injection into apolipoprotein E-deficient mice compared with nontargeted USPIO. In addition, atherosclerotic humanized LDLr −/− chimeras with leukocyte expression of human SR-AI showed a significant improvement in contrast-to-noise ratio (2.7-fold; P=0.003) in the atherosclerotic aortic arch plaques 24 hours after injection of SR-AI-targeted USPIO compared with chimeras with leukocyte SR-AI deficiency. Conclusions-Collectively, our data provide several lines of evidence that SR-AI-targeted molecular imaging of USPIO-based contrast agents holds great promise for in situ detection of inflammatory plaques in manifest atherosclerosis. Segers et al SR-AI-Targeted Molecular Imaging of Atherosclerosis 1813screening that displayed high affinity and specificity for SR-AI in vitro in murine and human macrophages. In vivo, PP1 has been shown to accumulate in macrophage-rich organs where it colocalized with F4/80+ macrophages and in atherosclerotic plaques. Furthermore, intravenous injected PP1-coupled fluorescent nanocrystals were successfully accumulated in advanced atherosclerotic plaques of apolipoprotein E-deficient (apoE −/− ) mice. 19In the current study, we report development and validation of SR-AI-targeted USPIO (T-USPIO) functionalized with the aforementioned SR-AI-specific peptide. The T-USPIO was validated in vitro on different mouse and human cell types found in atherosclerotic lesions and also in vivo in an established mouse model for atherosclerosis, as well as in a humanized model of atherosclerosis. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Relaxivity AnalysisThe contrast agent relaxivities were measured at 37°C at 20, 60, and 400 MHz, respectively (Table). The transverse relaxivities of the SR-A1 and control particle did not differ significantly nor did the longitudinal relaxivity. Increased Scavenger Receptor-AI-Mediated Uptake of T-USPIO In VitroThe kinetics of basal uptake, processing, and detection of USPIO in vitro and in vivo by macrophages have been the subject of numerous studies. 9 Here, we sought to investigate whether USPIO uptake by (plaque associated) macrophages could be augmented by conju...

Background-Adult human epicardium-derived cells (EPDCs), transplanted into the infarcted heart, are known to improve cardiac function, mainly through paracrine protection of the surrounding tissue. We hypothesized that this effect might be further improved if these supportive EPDCs were combined with cells that could possibly supply the ischemic heart with new cardiomyocytes. Therefore, we transplanted EPDCs together with cardiomyocyte progenitor cells that can generate mature cardiomyocytes in vitro. Methods and Results-EPDCs and cardiomyocyte progenitor cells were isolated from human adult atrial appendages, expanded in culture, and transplanted separately or together into the infarcted mouse myocardium (total cell number, 4ϫ10 5 ). Cardiac function was determined 6 weeks later (9.4T MRI). Coculturing increased proliferation rate and production of several growth factors, indicating a mutual effect. Cotransplantation resulted in further improvement of cardiac function compared with single cell-type recipients (PϽ0.05), which themselves demonstrated better function than vehicle-injected controls (PϽ0.05). However, in contrast to our hypothesis, no graft-derived cardiomyocytes were observed within the 6-week survival, supporting that not only EPDCs but also cardiomyocyte progenitor cells acted in a paracrine manner. Because injected cell number and degree of engraftment were similar between groups, the additional functional improvement in the cotransplantation group cannot be explained by an increased amount of secreted factors but rather by an altered type of secretion. Conclusion-EPDCs

Using VHH-Fc conjugates increases the blood half-life of the protein. However, purely extending the time window for brain uptake does not increase BBB passage. Nevertheless, VHH-Fc holds promise for therapeutic applications where a sustained systemic circulation of VHH is advantageous.

Conventional microscopic techniques, to study embryonic development, require large numbers of embryos and are invasive, making follow-up impossible. We explored the use of in vivo MRI to study embryonic development, in general, and cardiovascular development in particular, over time. Wild-type quail embryos (n = 11) were imaged at embryonic days 3, 5, 7, 9, and 11, covering the main time course of embryonic heart development. On each imaging day cardiac morphology was evaluated and embryonic length was measured. MRI-embryos as well as control embryos (n = 11) were sacrificed at day 11 and scored for external malformations, while embryonic wet weight and stage were determined. In addition, venous clipped embryos (n = 4), known to develop cardiovascular malformations, were scanned at regular intervals and sacrificed at day 9 for histological analysis ex vivo. We were able to follow heart development of individual quail embryos inside their shell non-invasively over time, with sufficient detail to study cardiac morphology in vivo. We did not find any adverse effect of the repeated MRI examinations on morphology, length, or weight. Prenatally diagnosed malformations, like ventricular septal defects and aortic arch interruptions were confirmed by histology. In conclusion, micro-MRI can be used to evaluate in vivo early embryonic development and to diagnose cardiovascular malformations prenatally.

Results show an initially bilateral electrical potential of sinus venosus myocardium evolving into a right-sided activation pattern during development, and suggest a role for RhoA in conduction system development. We hypothesize an initial sinus venosus-wide capacity to generate pacemaker signals, becoming confined to the definitive SAN. Lack of differentiation toward a chamber phenotype would explain ectopic pacemaker foci.