MEMRI is a biomarker defining nicotine-specific neuronal responses in subregions of the rodent brain.

Nicotine dependence is defined by dopaminergic neuronal activation within the nucleus accumbens (ACB) and by affected neural projections from nicotine-stimulated neurons. Control of any subsequent neural activities would underpin any smoking cessation strategy. While extensive efforts have been made to study the pathophysiology of nicotine addiction, more limited works were developed to find imaging biomarkers. If such biomarkers are made available, addictive behaviors could be monitored noninvasively. To such ends, we employed manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) to determine whether it could be used to monitor neuronal activities after acute and chronic nicotine exposure in rats. The following were observed. Mn(2+) infusion identified ACB and hippocampal (HIP) neuronal activities following acute nicotine administration. Chronic exposure was achieved by week long subcutaneously implanted nicotine mini-pump. Here nicotine was shown to activate neurons in the ACB, HIP, and the prefrontal and insular cortex. These are all central nervous system reward regions linked to drug addiction. In conclusion, MEMRI is demonstrated to be a powerful imaging tool to study brain subregion specific neuronal activities affected by nicotine. Thus, we posit that MEMRI could be used to assess smoking-associated tolerance, withdrawal and as such serve as a pre-clinical screening tool for addiction cessation strategies in humans

MiR-133a Mimic Alleviates T1DM-Induced Systolic Dysfunction in Akita: An MRI-Based Study

Diabetic cardiomyopathy is a leading cause of heart failure. Developing a novel therapeutic strategy for diabetic cardiomyopathy and characterizing animal models used for diabetes mellitus (DM) are important. Insulin 2 mutant (Ins2+/-) Akita is a spontaneous, genetic, mouse model for T1DM, which is relevant to humans. There are contrasting reports on systolic dysfunction and pathological remodeling (hypertrophy and fibrosis) in Akita heart. Here, we used magnetic resonance imaging (MRI) approach, a gold standard reference for evaluating cardiac function, to measure ejection fraction (indicator of systolic dysfunction) in Akita. Moreover, we performed Wheat Germ Agglutinin (WGA) and hematoxylin and Eosin stainings to determine cardiac hypertrophy, and Masson\u27s Trichrome and picrosirius red stainings to determine cardiac fibrosis in Akita. MiR-133a, an anti-hypertrophy and anti-fibrosis miRNA, is downregulated in Akita heart. We determined if miR-133a mimic treatment could mitigate systolic dysfunction and remodeling in Akita heart. Our MRI results revealed decreased ejection fraction in Akita as compared to WT and increased ejection fraction in miR-133a mimic-treated Akita. We also found that miR-133a mimic treatment mitigates T1DM-induced cardiac hypertrophy and fibrosis in Akita. We conclude that Akita shows cardiac hypertrophy, fibrosis and systolic dysfunction and miR-133a mimic treatment to Akita could ameliorate them

Landmark Optimization Using Local Curvature for Point-Based Nonlinear Rodent Brain Image Registration

Purpose. To develop a technique to automate landmark selection for point-based interpolating transformations for nonlinear medical image registration. Materials and Methods. Interpolating transformations were calculated from homologous point landmarks on the source (image to be transformed) and target (reference image). Point landmarks are placed at regular intervals on contours of anatomical features, and their positions are optimized along the contour surface by a function composed of curvature similarity and displacements of the homologous landmarks. The method was evaluated in two cases (n = 5 each). In one, MRI was registered to histological sections; in the second, geometric distortions in EPI MRI were corrected. Normalized mutual information and target registration error were calculated to compare the registration accuracy of the automatically and manually generated landmarks. Results. Statistical analyses demonstrated significant improvement (P < 0.05) in registration accuracy by landmark optimization in most data sets and trends towards improvement (P < 0.1) in others as compared to manual landmark selection

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery

Registered Bioimaging of Nanomaterials for Diagnostic and Therapeutic Monitoring

Nanomedications can be carried by blood borne monocyte-macrophages into the reticuloendothelial system (RES; spleen, liver, lymph nodes) and to end organs. The latter include the lung, RES, and brain and are operative during human immunodeficiency virus type one (HIV-1) infection. Macrophage entry into tissues is notable in areas of active HIV-1 replication and sites of inflammation. In order to assess the potential of macrophages as nanocarriers, superparamagnetic iron-oxide and/or drug laden particles coated with surfactants were parenterally injected into HIV-1 encephalitic mice. This was done to quantitatively assess particle and drug biodistribution. Magnetic resonance imaging (MRI) test results were validated by histological coregistration and enhanced image processing. End organ disease as typified by altered brain histology were assessed by MRI. The demonstration of robust migration of nanoformulations into areas of focal encephalitis provides '"proof of concept" for the use of advanced bioimaging techniques to monitor macrophage migration. Importantly, histopathological aberrations in brain correlate with bioimaging parameters making the general utility of MRI in studies of cell distribution in disease feasible. We posit that using such methods can provide a real time index of disease burden and therapeutic efficacy with translational potential to humans

Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson\u27s disease.

Nigrostriatal degeneration, the pathological hallmark of Parkinson\u27s disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease. We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease. When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished. MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals. Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections. These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD

Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy.

Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory\u27s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery

Quantitative diffusion tensor imaging detects dopaminergic neuronal degeneration in a murine model of Parkinson\u27s disease.

Early diagnosis of Parkinson\u27s disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect \u3e50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p\u3c0.005) and decreased fractional anisotropy (p\u3c0.03) in the substantia nigra (SN) of 5- to 7-day MPTP-treated animals when compared to saline controls. Transverse diffusivity demonstrated the most significant differences (p \u3c or = 0.002) and correlated with the numbers of SN dopaminergic neurons (r=-0.75, p=0.012). No differences were found in the striatum, corpus callosum, cerebral cortex, or ventricles. These results demonstrate that DTI may be used as a surrogate biomarker of nigral dopaminergic neuronal degeneration

Metabolic drift in the aging brain.

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, purine/pyrimidine accumulation) and significantly altered oxidative phosphorylation and nucleotide biosynthesis and degradation. The central energy metabolic drift suggests a failure of the cellular machinery to restore metabostasis (metabolite homeostasis) in the aged brain and therefore an inability to respond properly to external stimuli, likely driving the alterations in signaling activity and thus in neuronal function and communication

Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors

Metal-free magnetic resonance imaging (MRI) agents could overcome the established toxicity associated with metal-based agents in some patient populations and enable new modes of functional MRI in vivo. Herein, we report nitroxidefunctionalized brush-arm star polymer organic radical contrast agents (BASP-ORCAs) that overcome the low contrast and poor in vivo stability associated with nitroxide-based MRI contrast agents. As a consequence of their unique nanoarchitectures, BASP-ORCAs possess per-nitroxide transverse relaxivities up to ∼44-fold greater than common nitroxides, exceptional stability in highly reducing environments, and low toxicity. These features combine to provide for accumulation of a sufficient concentration of BASP-ORCA in murine subcutaneous tumors up to 20 h following systemic administration such that MRI contrast on par with metal-based agents is observed. BASP-ORCAs are, to our knowledge, the first nitroxide MRI contrast agents capable of tumor imaging over long time periods using clinical high-field 1H MRI techniques. Includes Supplementary materia