White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology

INTRODUCTION: An inactivating mutation in the MATERIALS AND METHODS: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in RESULTS: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain DISCUSSION: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. Th

Mapping Extracellular pH of Gliomas in Presence of Superparamagnetic Nanoparticles: Towards Imaging the Distribution of Drug-Containing Nanoparticles and Their Curative Effect on the Tumor Microenvironment

Since brain’s microvasculature is compromised in gliomas, intravenous injection of tumor-targeting nanoparticles containing drugs (D-NPs) and superparamagnetic iron oxide (SPIO-NPs) can deliver high payloads of drugs while allowing MRI to track drug distribution. However, therapeutic effect of D-NPs remains poorly investigated because superparamagnetic fields generated by SPIO-NPs perturb conventional MRI readouts. Because extracellular pH (pHe) is a tumor hallmark, mapping pHe is critical. Brain pHe is measured by biosensor imaging of redundant deviation in shifts (BIRDS) with lanthanide agents, by detecting paramagnetically shifted resonances of nonexchangeable protons on the agent. To test the hypothesis that BIRDS-based pHe readout remains uncompromised by presence of SPIO-NPs, we mapped pHe in glioma-bearing rats before and after SPIO-NPs infusion. While SPIO-NPs accumulation in the tumor enhanced MRI contrast, the pHe inside and outside the MRI-defined tumor boundary remained unchanged after SPIO-NPs infusion, regardless of the tumor type (9L versus RG2) or agent injection method (renal ligation versus coinfusion with probenecid). These results demonstrate that we can simultaneously and noninvasively image the specific location and the healing efficacy of D-NPs, where MRI contrast from SPIO-NPs can track their distribution and BIRDS-based pHe can map their therapeutic impact

Dendrimer-Based Responsive MRI Contrast Agents (G1–G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS)

Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1–G4), where the model dendrimer and chelate were based on poly­(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA^4–) complexed with thulium ion (Tm³⁺). Temperature sensitivities of two prominent signals of G<i>n</i>-PAMAM-(TmDOTA^–)_<i>x</i> (where <i>n</i> = 1–4, <i>x</i> = 6–39) were comparable to that of prominent signals in TmDOTA^–. Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA^–)_<i>x</i> were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA^–. A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)₁₂ to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors