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Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke.

ABSTRACT: The purpose of this study is to propose and validate a preclinical in vivo magnetic resonance imaging (MRI) tool to monitor neuroinflammation following ischemic stroke, based on injection of a novel multimodal nanoprobe, NanoGd, specifically designed for internalization by phagocytic cells. First, it is verified that NanoGd is efficiently internalized by microglia in vitro. In vivo MRI coupled with intravenous injection of NanoGd in a permanent middle cerebral artery occlusion mouse model results in hypointense signals in the ischemic lesion. In these mice, longitudinal two-photon intravital microscopy shows NanoGd internalization by activated CX3CR1-GFP/+ cells. Ex vivo analysis, including phase contrast imaging with synchrotron X-ray, histochemistry, and transmission electron microscopy corroborate NanoGd accumulation within the ischemic lesion and uptake by immune phagocytic cells. Taken together, these results confirm the potential of NanoGd-enhanced MRI as an imaging biomarker of neuroinflammation at the subacute stage of ischemic stroke. As far as it is known, this work is the first to decipher the working mechanism of MR signals induced by a nanoparticle passively targeted at phagocytic cells by performing intravital microscopy back-to-back with MRI. Furthermore, using a gadolinium-based rather than an iron-based contrast agent raises future perspectives for the development of molecular imaging with emerging computed tomography technologies.

SUBMITTER: Hubert V

PROVIDER: S-EPMC8425862 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Administration of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) has been demonstrated to alleviate infarction following ischemic stroke. Reportedly, the main effect of AUDA is exerting anti-inflammation and neovascularization via the inhibition of soluble epoxide hydrolase. However, the major contribution of this anti-inflammation and neovascularization effect in the acute phase of stroke is not completely elucidated. To investigate the neuroprotective effects of AUDA in acute ischemic stroke, we combined laser speckle contrast imaging and optical intrinsic signal imaging techniques with the implantation of a lab-designed cranial window. Forepaw stimulation was applied to assess the functional changes via measuring cerebral metabolic rate of oxygen (CMRO2) that accompany neural activity. The rats that received AUDA in the acute phase of photothrombotic ischemia stroke showed a 30.5 ± 8.1% reduction in the ischemic core, 42.3 ± 15.1% reduction in the ischemic penumbra (p < 0.05), and 42.1 ± 4.6% increase of CMRO2 in response to forepaw stimulation at post-stroke day 1 (p < 0.05) compared with the control group (N = 10 for each group). Moreover, at post-stroke day 3, increased functional vascular density was observed in AUDA-treated rats (35.9 ± 1.9% higher than that in the control group, p < 0.05). At post-stroke day 7, a 105.4% ± 16.4% increase of astrocytes (p < 0.01), 30.0 ± 10.9% increase of neurons (p < 0.01), and 65.5 ± 15.0% decrease of microglia (p < 0.01) were observed in the penumbra region in AUDA-treated rats (N = 5 for each group). These results suggested that AUDA affects the anti-inflammation at the beginning of ischemic injury and restores neuronal metabolic rate of O2 and tissue viability. The neovascularization triggered by AUDA restored CBF and may contribute to ischemic infarction reduction at post-stroke day 3. Moreover, for long-term neuroprotection, astrocytes in the penumbra region may play an important role in protecting neurons from apoptotic injury.

Project description:ImportanceThe potential association of schizophrenia with distinct retinal changes is of clinical interest but has been challenging to investigate because of a lack of sufficiently large and detailed cohorts.ObjectiveTo investigate the association between retinal biomarkers from multimodal imaging (oculomics) and schizophrenia in a large real-world population.Design, setting, and participantsThis cross-sectional analysis used data from a retrospective cohort of 154 830 patients 40 years and older from the AlzEye study, which linked ophthalmic data with hospital admission data across England. Patients attended Moorfields Eye Hospital, a secondary care ophthalmic hospital with a principal central site, 4 district hubs, and 5 satellite clinics in and around London, United Kingdom, and had retinal imaging during the study period (January 2008 and April 2018). Data were analyzed from January 2022 to July 2022.Main outcomes and measuresRetinovascular and optic nerve indices were computed from color fundus photography. Macular retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (mGC-IPL) thicknesses were extracted from optical coherence tomography. Linear mixed-effects models were used to examine the association between schizophrenia and retinal biomarkers.ResultsA total of 485 individuals (747 eyes) with schizophrenia (mean [SD] age, 64.9 years [12.2]; 258 [53.2%] female) and 100 931 individuals (165 400 eyes) without schizophrenia (mean age, 65.9 years [13.7]; 53 253 [52.8%] female) were included after images underwent quality control and potentially confounding conditions were excluded. Individuals with schizophrenia were more likely to have hypertension (407 [83.9%] vs 49 971 [48.0%]) and diabetes (364 [75.1%] vs 28 762 [27.6%]). The schizophrenia group had thinner mGC-IPL (-4.05 μm, 95% CI, -5.40 to -2.69; P = 5.4 × 10-9), which persisted when investigating only patients without diabetes (-3.99 μm; 95% CI, -6.67 to -1.30; P = .004) or just those 55 years and younger (-2.90 μm; 95% CI, -5.55 to -0.24; P = .03). On adjusted analysis, retinal fractal dimension among vascular variables was reduced in individuals with schizophrenia (-0.14 units; 95% CI, -0.22 to -0.05; P = .001), although this was not present when excluding patients with diabetes.Conclusions and relevanceIn this study, patients with schizophrenia had measurable differences in neural and vascular integrity of the retina. Differences in retinal vasculature were mostly secondary to the higher prevalence of diabetes and hypertension in patients with schizophrenia. The role of retinal features as adjunct outcomes in patients with schizophrenia warrants further investigation.

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Multimodal Imaging with NanoGd Reveals Spatiotemporal Features of Neuroinflammation after Experimental Stroke.

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