MRI/PET multimodal imaging of the innate immune response in skeletal muscle and draining lymph node post vaccination in rats.

The goal of this study was to utilize a multimodal magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging approach to assess the local innate immune response in skeletal muscle and draining lymph node following vaccination in rats using two different vaccine platforms (AS01 adjuvanted protein and lipid nanoparticle (LNP) encapsulated Self-Amplifying mRNA (SAM)). MRI and 18FDG PET imaging were performed temporally at baseline, 4, 24, 48, and 72 hr post Prime and Prime-Boost vaccination in hindlimb with Cytomegalovirus (CMV) gB and pentamer proteins formulated with AS01, LNP encapsulated CMV gB protein-encoding SAM (CMV SAM), AS01 or with LNP carrier controls. Both CMV AS01 and CMV SAM resulted in a rapid MRI and PET signal enhancement in hindlimb muscles and draining popliteal lymph node reflecting innate and possibly adaptive immune response. MRI signal enhancement and total 18FDG uptake observed in the hindlimb was greater in the CMV SAM vs CMV AS01 group (↑2.3 - 4.3-fold in AUC) and the MRI signal enhancement peak and duration were temporally shifted right in the CMV SAM group following both Prime and Prime-Boost administration. While cytokine profiles were similar among groups, there was good temporal correlation only between IL-6, IL-13, and MRI/PET endpoints. Imaging mass cytometry was performed on lymph node sections at 72 hr post Prime and Prime-Boost vaccination to characterize the innate and adaptive immune cell signatures. Cell proximity analysis indicated that each follicular dendritic cell interacted with more follicular B cells in the CMV AS01 than in the CMV SAM group, supporting the stronger humoral immune response observed in the CMV AS01 group. A strong correlation between lymph node MRI T2 value and nearest-neighbor analysis of follicular dendritic cell and follicular B cells was observed (r=0.808, P<0.01). These data suggest that spatiotemporal imaging data together with AI/ML approaches may help establish whether in vivo imaging biomarkers can predict local and systemic immune responses following vaccination.

Superparamagnetic nanoparticle-enhanced MRI of Alzheimer's disease plaques and activated microglia in 3X transgenic mouse brains: Contrast optimization.

PURPOSE: To optimize magnetic resonance imaging (MRI) of antibody-conjugated superparamagnetic nanoparticles for detecting amyloid-ß plaques and activated microglia in a 3X transgenic mouse model of Alzheimer's disease. MATERIALS AND METHODS: Ten 3X Tg mice were fed either chow or chow containing 100 ppm resveratrol. Four brains, selected from animals injected with either anti-amyloid targeted superparamagnetic iron oxide nanoparticles, or anti-Iba-1-conjugated FePt-nanoparticles, were excised, fixed with formalin, and placed in Fomblin for ex vivo MRI (11.7T) using multislice-multiecho, multiple gradient echo, rapid acquisition with relaxation enhancement, and susceptibility-weighted imaging (SWI). Aß plaques and areas of neuroinflammation appeared as hypointense regions whose number, location, and Z-score were measured as a function of sequence type and echo time. RESULTS: The MR contrast was due to the shortening of the transverse relaxation time of the plaque-adjacent tissue water. A theoretical analysis of this effect showed that the echo time was the primary determinant of plaque contrast and was used to optimize Z-scores. The Z-scores of the detected lesions varied from 21 to 34 as the echo times varied from 4 to 25 msec, with SWI providing the highest Z-score and number of detected lesions. Computation of the entire plaque and activated microglial distributions in 3D showed that resveratrol treatment led to a reduction of ∼24-fold of Aß plaque density and ∼4-fold in microglial activation. CONCLUSION: Optimized MRI of antibody-conjugated superparamagnetic nanoparticles served to reveal the 3D distributions of both Aß plaques and activated microglia and to measure the effects of drug treatments in this 3X Tg model. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:574-588.

Diffusion tensor imaging of in vivo and excised rat spinal cord at 7 T with an icosahedral encoding scheme.

Regional values of fractional anisotropy (FA) and mean diffusivity (D(av)) of in vivo and excised rat spinal cords were measured using an iscosahedral encoding scheme that is based on 21 uniformly distributed and alternating gradient directions with an echo planar imaging (EPI) readout. Based on the water phantom studies, this scheme was shown to provide unbiased estimation of FA. The stability of the scanner during the acquisition of diffusion tensor imaging (DTI) data was evaluated. Repeated measurements of the FA values demonstrated excellent reproducibility, as assessed by the Bland-Altman analysis. These studies demonstrated a reduced anisotropy in excised samples relative to in vivo cords. Diffusion in the spinal cord gray matter was shown to be anisotropic. The FA value in the dorsal white matter (WM) was found to be higher relative to the ventral WM. Results from these studies should provide the necessary baseline data for serial in vivo DTI of injured spinal cord.

The brain's response to incidental intruded words during focal text processing.

The functional neuroanatomy associated with processing single words incidentally, outside focal attention, was investigated. We asked subjects (n = 15) to listen, focus on, and comprehend a story narrative, and then single, unrelated but meaningful words were intruded into the ongoing narrative. We also manipulated the type of intruded word, using either neutral or emotionally valent words, to evaluate the extent of semantic processing and a potential encoding advantage for one type of material. Analyses emphasized the areas of activation unique to the intruded words as distinguished from the narrative text. Subjects were normal, healthy adults (n = 15). Compared to narrative text, the intruded words were associated with activation in the right middle temporal gyrus (BA 39) and posterior cingulate/precuneus regions (BA 30, 23). We conclude that the intruded words did make contact with word-level lexical but not necessarily semantic structures in the middle temporal region. The data suggested that the intruded words were processed by a "nonexecutive" monitoring system implemented by a pairing of activation in posterior, medial structures such as the posterior cingulate with deactivation in brain stem structures. This pattern induced a shift to more passive, less effortful, nonstrategic monitoring of the words. Thus, attention processing, not semantic processing, changes best characterized the brain activation unique to the intruded words. This posterior, medial region is discussed as a substrate dedicated to processing a second, incidental stream of information and thereby providing a crucial mechanism for implementing dual processing of the kind examined here.