Iron accumulation in microglia has been observed in Alzheimer's disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms, including neuroinflammation. To study this interaction, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with iron, in combination with inflammatory stimuli such as interferon gamma (IFN-γ) and amyloid β. Both IFN-γ and iron treatment increased labile iron levels, but only iron treatment led to a consistent increase of ferritin levels, reflecting long-term iron storage. Therefore, in iPSC-MG, ferritin appeared to be regulated by iron revels rather than inflammation. Further investigation showed that while IFN-γ induced pro-inflammatory activation, iron treatment dampened both classic pro- and anti-inflammatory activation on a transcriptomic level. Notably, iron-loaded microglia showed strong upregulation of cellular stress response pathways, the NRF2 pathway, and other oxidative stress pathways. Functionally, iPSC-MG exhibited altered phagocytosis and impaired mitochondrial metabolism following iron treatment. Collectively, these data suggest that in MG, in contrast to current hypotheses, iron treatment does not result in pro-inflammatory activation, but rather dampens it and induces oxidative stress.
Abstract 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. -weighted MRI was performed on post-mortem cortical tissue of controls, late-onset AD, and early-onset AD followed by histology and correlation analyses. Combining ex-vivo high-resolution MRI and histopathology revealed that: 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. Abbreviations AD Alzheimer’s disease EOAD early-onset AD GM gray matter IRP iron regulating proteins LOAD late-onset AD MCI mild cognitive impairment PBS phosphate buffered saline QSM quantitative susceptibility mapping WM white matter
In the foreseeable future, the MI field could greatly assist neuroradiologists. Reporter molecules provide information on specific molecular or cellular events that could not only aid diagnosis but potentially differentiate stages of disorders and treatments. To accomplish this, reporter molecules literally need to pass a barrier, the BBB, which is designed to repel nonessential molecules from the brain. Although this is not a trivial task, several transport systems could be tricked into guiding molecules into the brain. The noninvasive nature in conjunction with a wide availability makes MR imaging particularly suitable for longitudinal neurologic imaging studies. This review explains the principles of MR imaging contrast, delineates different types of reporter molecules, and describes strategies to transport reporters into the brain. It also discusses recent advances in MR imaging hardware, pulse sequences, the development of targeted reporter probes, and future directions of the MR neuroimaging field.
Background: Although mice are used extensively to study atherosclerosis of different vascular beds, limited data is published on the occurrence of intracranial atherosclerosis. Since intracranial atherosclerosis is a common cause of stroke and is associated with dementia, a relevant animal model is needed to study these diseases. Methods and results: We examined the presence of intracranial atherosclerosis in different atherogenic mouse strains and studied differences in vessel wall characteristics in mouse and human tissue in search for possible explanations for the different atherosclerotic susceptibility between extracranial and intracranial vessels. The presence of atherosclerotic plaques was systematically examined from the distal common carotids to the circle of Willis in three atherogenic mouse models. Extra- and intracranial vessel characteristics were studied by immunohistochemistry. All three strains developed atherosclerotic lesions in the common carotids, while no lesions were found intracranially. This coincided with altered vessel morphology. Compared to extracranial sections, intracranially the number of elastic layers decreased, tight junction markers increased and antioxidant enzyme heme oxygenase (HO)-1 increased. Higher HO-1 expression was also shown in human intracranial arteries. Human brain endothelial cell stimulation with oxLDL induced endogenous protective antioxidant HO-1 levels through Nrf2 translocation. Conclusion: Intracranial atherosclerosis was absent in three atherogenic mouse models. Intracranial vessel segments showed increased presence of junction markers in mice and increased HO-1 in both mice and human tissue. We suggest that differences in brain vessel structure and induced antioxidant levels in the brain endothelium found in mouse and human tissue may contribute to decreased atherosclerosis susceptibility of intracranial arteries.
Segmentation of magnetic resonance imaging (MRI) data is required for many applications, such as the comparison of different structures or time points, and for annotation purposes. Currently, the gold standard for automated image segmentation is nonlinear atlas-based segmentation. However, these methods are either not sufficient or highly time consuming for mouse brains, owing to the low signal to noise ratio and low contrast between structures compared with other applications. We present a novel generic approach to reduce processing time for segmentation of various structures of mouse brains, in vivo and ex vivo. The segmentation consists of a rough affine registration to a template followed by a clustering approach to refine the rough segmentation near the edges. Compared with manual segmentations, the presented segmentation method has an average kappa index of 0.7 for 7 of 12 structures in in vivo MRI and 11 of 12 structures in ex vivo MRI. Furthermore, we found that these results were equal to the performance of a nonlinear segmentation method, but with the advantage of being 8 times faster. The presented automatic segmentation method is quick and intuitive and can be used for image registration, volume quantification of structures, and annotation.
Cerebrospinal fluid (CSF) enhancement on T2-weighted post-contrast fluid-attenuated inversion recovery (pcT2wFLAIR) images is a relatively unknown neuroradiological marker for gadolinium-based contrast agent extravasation due to blood–brain barrier (BBB) disruption. We systematically reviewed human studies reporting on CSF enhancement on pcT2wFLAIR images to provide a comprehensive overview of prevalence of this new biomarker in healthy and diseased populations as well as its etiology and optimal detection methodology. We extracted information on the prevalence of CSF enhancement, its vascular risk factor and neuroimaging correlates, and methodological attributes of each study. Forty-four eligible studies were identified. By pooling data, we found that the prevalence of CSF enhancement was 82% (95% confidence interval (CI) 80–89) in meningitis (4 studies, 65 patients), 73% (95%CI 62–81) in cases with (post-) acute intracerebral hemorrhage (2 studies, 77 cases), 64% (95% CI 54–73) in cases who underwent surgery for aneurysm treatment (2 studies, 99 patients), 40% (95% CI 30–51) in cases who underwent surgery for carotid artery disease treatment (3 studies, 76 patients), 27% (95% CI 25–30) in cases with acute ischemic stroke (9 studies, 1148 patients), 21% (95% CI 17–23) in multiple sclerosis (6 studies, 897 patients), and 13% (95% CI 7–21) in adult controls (4 studies, 112 cases). Presence of CSF enhancement was associated with higher age in eleven studies, with lobar cerebral microbleeds in one study, and with cerebral atrophy in four studies. PcT2wFLAIR imaging represents a promising method that can provide novel perspectives on BBB leakage into CSF compartments, with the potential to reveal important new insights into the pathophysiological mechanisms of varying neurological diseases.
