Assessment of complementary white matter microstructural changes and grey matter atrophy in a preclinical model of Alzheimer's disease.

Alzheimer's disease (AD) has been associated with amyloid and tau pathology, as well as neurodegeneration. Beyond these hallmark features, white matter microstructural abnormalities have been observed using MRI. The objective of this study was to assess grey matter atrophy and white matter microstructural changes in a preclinical mouse model of AD (3xTg-AD) using voxel-based morphometry (VBM) and free-water (FW) diffusion tensor imaging (FW-DTI). Compared to controls, lower grey matter density was observed in the 3xTg-AD model, corresponding to the small clusters in the caudate-putamen, hypothalamus, and cortex. DTI-based fractional anisotropy (FA) was decreased in the 3xTg model, while the FW index was increased. Notably, the largest clusters for both FW-FA and FW index were in the fimbria, with other regions including the anterior commissure, corpus callosum, forebrain septum, and internal capsule. Additionally, the presence of amyloid and tau in the 3xTg model was confirmed with histopathology, with significantly higher levels observed across many regions of the brain. Taken together, these results are consistent with subtle neurodegenerative and white matter microstructural changes in the 3xTg-AD model that manifest as increased FW, decreased FW-FA, and decreased grey matter density.

Longitudinal evaluation of myofiber microstructural changes in a preclinical ALS model using the transverse relaxivity at tracer equilibrium (TRATE): A preliminary study.

T2⁎ relaxivity contrast imaging may serve as a potential imaging biomarker for amyotrophic lateral sclerosis (ALS) by noninvasively quantifying the tissue microstructure. In this preliminary longitudinal study, we investigated the Transverse Relaxivity at Tracer Equilibrium (TRATE) in three muscle groups between SOD1-G93A (ALS model) rat and a control population at two different timepoints. The control group was time matched to the ALS group such that the second timepoint was the onset of disease. We observed a statistically significant decrease in TRATE over time in the gastrocnemius, tibialis, and digital flexor muscles in the SOD1-G93A model (p-value = 0.003, 0.008, 0.005; respectively), whereas TRATE did not change over time in the control group (p-value = 0.4777, 0.6837, 0.9682; respectively). Immunofluorescent staining revealed a decrease in minimum fiber area and cell density in the SOD1-G93A model when compared to the control group (p-value = 6.043E-10 and 2.265E-10, respectively). These microstructural changes observed from histology align with the theorized biophysical properties of TRATE. We demonstrate that TRATE can longitudinally differentiate disease associated atrophy from healthy muscle and has potential to serve as a biomarker for disease progression and ultimately therapy response in patients with ALS.

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors.

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.

Molecular Imaging of Glucose Metabolism for Intraoperative Fluorescence Guidance During Glioma Surgery.

PURPOSE: This study evaluated the use of molecular imaging of fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as a discriminatory marker for intraoperative tumor border identification in a murine glioma model. PROCEDURES: 2-NBDG was assessed in GL261 and U251 orthotopic tumor-bearing mice. Intraoperative fluorescence of topical and intravenous 2-NBDG in normal and tumor regions was assessed with an operating microscope, handheld confocal laser scanning endomicroscope (CLE), and benchtop confocal laser scanning microscope (LSM). Additionally, 2-NBDG fluorescence in tumors was compared with 5-aminolevulinic acid-induced protoporphyrin IX fluorescence. RESULTS: Intravenously administered 2-NBDG was detectable in brain tumor and absent in contralateral normal brain parenchyma on wide-field operating microscope imaging. Intraoperative and benchtop CLE showed preferential 2-NBDG accumulation in the cytoplasm of glioma cells (mean [SD] tumor-to-background ratio of 2.76 [0.43]). Topically administered 2-NBDG did not create sufficient tumor-background contrast for wide-field operating microscope imaging or under benchtop LSM (mean [SD] tumor-to-background ratio 1.42 [0.72]). However, topical 2-NBDG did create sufficient contrast to evaluate cellular tissue architecture and differentiate tumor cells from normal brain parenchyma. Protoporphyrin IX imaging resulted in a more specific delineation of gross tumor margins than intravenous or topical 2-NBDG and a significantly higher tumor-to-normal-brain fluorescence intensity ratio. CONCLUSION: After intravenous administration, 2-NBDG selectively accumulated in the experimental brain tumors and provided bright contrast under wide-field fluorescence imaging with a clinical-grade operating microscope. Topical 2-NBDG was able to create a sufficient contrast to differentiate tumor from normal brain cells on the basis of visualization of cellular architecture with CLE. 5-Aminolevulinic acid demonstrated superior specificity in outlining tumor margins and significantly higher tumor background contrast. Given the nontoxicity of 2-NBDG, its use as a topical molecular marker for noninvasive in vivo intraoperative microscopy is encouraging and warrants further clinical evaluation.

4. The use and misuse of performance-enhancing substances in sport.

Doctors need to know if a patient is an athlete subject to drug testing, and to be aware of the legal situation surrounding drugs they prescribe such patients. Antidoping laws generally exist in order to provide a safe and fair environment for participation in sport. These laws should prevent and protect athletes from subjecting themselves to health risks through the use of unsafe, but performance-enhancing drugs. Because of difficulties in proving intent to cheat, the World Anti-Doping Agency enforces a principle of strict liability for positive test results for banned substances. An area of major controversy with respect to liability is the "sports supplement" industry, which is poorly regulated when compared with prescription drugs yet is a potential source of doping violations. Medical practitioners can be found guilty of anti-doping violations if they traffic banned drugs, prescribe these to athletes or otherwise assist athletes in taking banned substances. Medical practitioners are also now required to complete paperwork (therapeutic use exemption forms) to enable athletes to take banned substances which are required on medical grounds for specific illnesses.