Multiparametric magnetic resonance imaging for detection of pathological changes in the central nervous system of a mouse model of multiple sclerosis in vivo.

Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4-T magnetic resonance imaging (MRI). Multiparametric MRI measurements including MR spectroscopy, diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared with healthy mice, EAE mice showed a significant reduction in N-acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed a significant reduction in fractional anisotropy and axial diffusivity and an increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM), fractional anisotropy increased. High-resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2-L6), particularly WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo.

Cetuximab Exhibits Sex Differences in Lymphatic Exposure after Intravenous Administration in Rats in the Absence of Differences in Plasma Exposure.

PURPOSE: The aim of this work was to identify whether biochemical and physiological sources of mAb pharmacokinetic sex-effects could be identified in the rat model where target-mediated disposition is avoided. METHODS: Plasma and lymphatic pharmacokinetics of the humanised anti-EGFR antibody cetuximab, along with potential physiological and biochemical drivers of pharmacokinetic sex differences, were examined in male and female rats. Cetuximab was used as a model mAb since plasma clearance is slower in female patients. RESULTS: When plasma concentrations were normalised to dose, female rats displayed slower plasma clearance than males, but no significant differences were observed in liver and spleen biodistribution. Sex differences in apparent plasma clearance, however, were abolished after normalisation to body weight, surface area or fat-free mass. Significant sex differences were observed in plasma testosterone, endogenous IgG and fat free mass, but did not correlate with apparent clearance. Females did, however, show two-fold higher lymphatic exposure compared to males. CONCLUSIONS: These data suggested that mAbs more efficiently access lymph in females, but this does not affect plasma pharmacokinetics or biodistribution. Further, the data suggest that sex differences observed in humans could be a function of antigen density.

Spinal cord injury is not a feature of chronic whiplash-associated disorder: a magnetic resonance spectroscopy study.

PURPOSE: Injury to the cervical spinal cord has been suggested as a mechanism that may underpin chronic whiplash-associated disorder (WAD). This study aimed to assess metabolite concentrations indicative of neuronal injury or pathology in the cervical cord in people with chronic WAD. METHODS: Forty-one people with chronic WAD (mean [SD] age 39.6 [11.0] years, 25 females) and 14 healthy controls (39.2 [12.6] years, 9 females) underwent cervical spinal cord magnetic resonance spectroscopy to measure the metabolites N-acetylaspartate (NAA), creatine (Cr) and choline (Cho). Participants with WAD completed clinical questionnaires on pain intensity (Visual Analogue Scale), disability (Neck Disability Index) and psychological factors (Pain Catastrophising Scale, Post-traumatic Diagnostic Scale), and underwent cervical range of motion assessment and pain threshold testing to cold and pressure stimuli. Data were analysed using hypothesis testing and Spearman correlations (p < 0.05). RESULTS: There were no differences between the WAD and control groups for NAA/Cr (median [IQR] WAD 1.73 [1.38, 1.97], controls 2.09 [1.28, 2.89], p = 0.37), NAA/Cho (WAD 1.50 [1.18, 2.01], controls 1.57 [1.26, 1.93], p = 0.91) or Cr/Cho (WAD 0.84 [0.64, 1.17], controls 0.76 [0.60, 0.91], p = 0.33). There were no significant correlations between NAA/Cr, NAA/Cho or Cr/Cho and any clinical variable (p ≥ 0.06). CONCLUSIONS: Findings are consistent with major metabolic changes not being present in chronic WAD.

Magnetic resonance spin-spin relaxation time estimation in a rat model of fatty liver disease.

PURPOSE: To compare mono- and bi-exponential relaxation model equations to discriminate between normal and fatty liver disease. MATERIALS AND METHODS: Six rats on a choline deficient amino acid modified (CDAA) diet and six on normal chow were studied. Multiple spin echo images with increasing echo times (TEs) were collected at 9.4T. Pixel-wise T2 maps were generated using mono-exponential decay function to calculate T2M , and a bi-exponential to calculate, short T2 component (T2S ), long T2 component (T2L ), and fractions of these components (ρS , ρL ), respectively. Statistical F-tests and Akaike's information criterion (AIC) were used to assess the relative performance of the two models. RESULTS: F-test and AIC showed that in the CDAA group, T2 bi-exponential model described the signal of T2 weighted imaging of the liver better than the mono-exponential model. Controls were best described by the mono-exponential model. Mean values for T2M , T2L , T2S , ρS , ρL were 31.2 ± 0.7 ms, 72.8 ± 3.3 ms, 8.2 ± 0.6 ms,71.2 ± 2.1%, 30.4 ± 1.3%, respectively, in CDAA rats, compared with 18.8 ± 0.5 ms, 32.3 ± 0.7 ms, 9.2 ± 1.8 ms, 79 ± 2%, 21.0 ± 1.1% in controls. CONCLUSION: In the fatty liver of CDAA rats we have shown that T2 weighted images fit the bi-exponential model better than mono-exponential decays thus providing a better description of the data. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:468-476.

Spinal multiparametric MRI and DEXA changes over time in men with prostate cancer treated with androgen deprivation therapy: a potential imaging biomarker of treatment toxicity.

OBJECTIVES: To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). METHODS: Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12 months. L-spine MRI was done at baseline and 6 months. RESULTS: The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1 %/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p < 0.0001) and a negative correlation between MRS FF and ADC (r = -0.56, p = 0.036). Over 6 months, MRS FF increased by a median of 25 % in relative values (p = 0.0003), Dixon FF increased (p < 0.0001) and ADC values decreased (p = 0.0014). Men with >5 % BMD loss after 1 year had triple the percentage increase in MRS FF at 6 months (61.1 % vs. 20.9 %, p = 0.19). CONCLUSIONS: Changes are observed on L-spine MRI after 6 months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. KEY POINTS: • Spinal marrow fat fraction increases after 6 months of androgen deprivation therapy. • More inferior vertebral bodies tend to have higher fat fractions. • MRS fat fraction changes were associated with later changes in DEXA BMD.

A USPIO doped gel phantom for R2* relaxometry.

OBJECTIVE: This work describes a phantom containing regions of controlled R2* (1/T2*) values to provide a stable reference object for testing implementations of R2* relaxometry commonly used for liver and heart iron assessments. MATERIALS AND METHODS: A carrageenan-strengthened gadolinium DTPA doped agarose gel was used to enclose nine gels additionally doped with ultra-small superparamagnetic iron oxide. R2* values were determined at 1.5 T using multi-echo GRE sequences and exponential regression of pixel values from a region of interest against echo time using non-linear regression algorithms. We measured R2*, R2 and R1 values and the inter-scan and inter-operator reproducibility. RESULTS: The phantom reliably demonstrated R2* values in seven steps between 22.4 s-1 (SE 1.98) and 441.9 s-1 (SE 6.76), with an R2* relaxivity (r2*) of 792 (SE 5.6) mM-1 s-1. The doped gels displayed a concentration-dependent R2' component of R2* phantom, indicating superparamagnetic enhancement effects. We observed no significant change in relaxivity (r2*) over 12 months, and estimate a useful life of 3 years. Detailed descriptions of the production process and calculators are been provided as Online Resources. CONCLUSION: The phantom provides a durable test object with controlled R2* relaxation behaviour, useful for a range of R2* relaxometry reference work.

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue.

The Rar-related orphan receptor-α (Rorα) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rorα-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Rorα-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Pparα, Errα, Dio2, Acot11/Bfit, Cpt1ß, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesity-resistant phenotype in Rorα-deficient mice.

EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study.

Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with 64Cu through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-64Cu images were qualitatively and quantitatively compared to the current clinical standards of [18F]FDOPA and gadolinium (Gd) contrast-enhanced MRI. We show that EphA2-4B3-NOTA-64Cu effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-64Cu images than in [18F]FDOPA images and Gd contrast-enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG.

Microscopic diffusion properties of fixed breast tissue: Preliminary findings.

PURPOSE: To investigate the microscopic diffusion properties of formalin-fixed breast tissue. METHODS: Diffusion microimaging was performed at 16.4T with 40-µm isotropic voxels on two normal and two cancer tissue samples from four patients. Results were correlated with histology of the samples. RESULTS: Diffusion-weighted images and mean diffusivity maps demonstrated distinct diffusivity differences between breast tissue components. Mean diffusivity (MD) in normal tissue was 0.59 ± 0.24 µm(2) /ms for gland lobule (voxels containing epithelium and intralobular stroma) and 1.23 ± 0.34 µm(2) /ms for interlobular fibrous stroma. In the cancer samples, MD = 0.45 ± 0.23 µm(2) /ms for invasive ductal carcinoma (voxels contain epithelium and intralobular stroma) and 0.61 ± 0.35 µm(2) /ms for ductal carcinoma in situ. There were significant MD differences between all tissue components (P < 0.005), except between gland lobule and ductal carcinoma in situ (P = 0.71). The low diffusivity of epithelium-rich cancer tissue and of normal epithelium relative to its supporting fibrous stroma was similar to that reported for prostate tissue and the esophageal wall. CONCLUSION: Diffusion microimaging demonstrates distinct diffusivity differences between breast tissue glandular structures. Low diffusivity may be a distinctive feature of mammalian epithelia.

Resveratrol does not benefit patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS: Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS: Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS: Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

Multifunctional Fluoropolymer-Engineered Magnetic Nanoparticles to Facilitate Blood-Brain Barrier Penetration and Effective Gene Silencing in Medulloblastoma.

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma.

Longitudinal assessment of white matter pathology in the injured mouse spinal cord through ultra-high field (16.4 T) in vivo diffusion tensor imaging.

This study examined the sensitivity of ultra-high field (16.4 T) diffusion tensor imaging (DTI; 70 µm in-plane resolution, 1mm slice thickness) to evaluate the spatiotemporal development of severe mid-thoracic contusive spinal cord injury (SCI) in mice. In vivo imaging was performed prior to SCI, then again at 2h, 1 day, 3 days, 7 days, and 30 days post-SCI using a Bruker 16.4 T small animal nuclear magnetic resonance spectrometer. Cross-sectional spinal cord areas were measured in axial slices and various DTI parameters, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ||) and radial diffusivity (λ⊥), were calculated for the total spared white matter (WM), ventral funiculi (VF), lateral funiculi (LF) and dorsal columns (DCs) and then correlated with histopathology. Cross-sectional area measurements revealed significant atrophy (32% reduction) of the injured spinal cord at the lesion epicentre in the chronic phase of injury. Analysis of diffusion tensor parameters further showed that tissue integrity was most severely affected in the DCs, i.e. the site of immediate impact, which demonstrated a rapid and permanent decrease in FA and λ||. In contrast, DTI parameters for the ventrolateral white matter changed more gradually with time, suggesting that these regions are undergoing more delayed degeneration in a manner that may be amenable to therapeutic intervention. Of all the DTI parameters, λ⊥ was most closely correlated to myelin content whereas changes in FA and λ|| appeared more indicative of axonal integrity, Wallerian degeneration and associated presence of macrophages. We conclude that longitudinal DTI at 16.4T provides a clinically relevant, objective measure for assessing white matter pathology following contusive SCI in mice that may aid the translation of putative neuroprotective strategies into the clinic.

Vertebral landmarks for the identification of spinal cord segments in the mouse.

Accurate identification of spinal cord segments in relation to vertebral landmarks is essential to surgery aimed at experimental spinal cord injury. We have analyzed a complete series of high-resolution magnetic resonance (MR) images from the mouse spine in order to delineate the boundaries of spinal cord segments in relation to vertebral landmarks. The resulting atlas can be used to plan experimental approaches that require the accurate identification of a target spinal cord segment.

Detection of endogenous iron deposits in the injured mouse spinal cord through high-resolution ex vivo and in vivo MRI.

The main aim of this study was to employ high-resolution MRI to investigate the spatiotemporal development of pathological features associated with contusive spinal cord injury (SCI) in mice. Experimental mice were subjected to either sham surgery or moderate contusive SCI. A 16.4-T small-animal MR system was employed for nondestructive imaging of post-mortem, fixed spinal cord specimens at the subacute (7 days) and more chronic (28-35 days) stages post-injury. Routine histological techniques were used for subsequent investigation of the observed neuropathology at the microscopic level. The central core of the lesion appeared as a dark hypo-intense area on MR images at all time points investigated. Small focal hypo-intense spots were also observed spreading through the dorsal funiculi proximal and distal to the site of impact, an area that is known to undergo gliosis and Wallerian degeneration in response to injury. Histological examination revealed these hypo-intense spots to be high in iron content as determined by Prussian blue staining. Quantitative image analysis confirmed the increased presence of iron deposits at all post-injury time points investigated (p<0.05). Distant iron deposits were also detectable through live imaging without the use of contrast-enhancing agents, enabling the longitudinal investigation of this pathology in individual animals. Further immunohistochemical evaluation showed that intracellular iron deposits localised to macrophages/microglia, astrocytes and oligodendrocytes in the subacute phase of SCI, but predominantly to glial fibrillary acidic protein-positive, CC-1-positive astrocytes at later stages of recovery. Progressive, widespread intracellular iron accumulation is thus a normal feature of SCI in mice, and high-resolution MRI can be effectively used to detect and monitor these neuropathological changes with time.

Non-invasive monitoring of sucrose mobilization from culm storage parenchyma by magnetic resonance spectroscopy.

Because sucrose stored in mature stalks (in excess of 40% of stalk dry weight) can be wholly mobilized to supply carbon for the growth of heterotrophic tissues, we propose that sucrose mobilization requires a net sink-to-source transition that acts in toto within sett internode storage parenchyma. Based on our data we propose that mobilization of sucrose from culm storage parenchyma requires minimal investment of metabolic resources, and that the mechanism of sucrose mobilization is metabolically neutral. By magnetic resonance spectroscopy and phloem-specific tracer dyes, strong evidence was found that sucrose is mobilized from sett storage parenchyma via phloem to the growing shoot tissue. An analysis of the enzyme activities involved in sucrose metabolism and glycolysis suggested that sucrose synthase activity is downregulated due to the effects of sucrose mobilization. Overall, metabolism in storage parenchyma shifts from futile cycling to a more quiescent state during sucrose mobilization.

Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands.

Several classes of cannabinoid receptor type 2 radioligands have been evaluated for imaging of neuroinflammation, with successful clinical translation yet to take place. Here we describe the synthesis of fluorinated 5-azaindoles and pharmacological characterization and in vivo evaluation of 18F-radiolabeled analogues. [18F]2 (hCB2 Ki = 96.5 nM) and [18F]9 (hCB2 Ki = 7.7 nM) were prepared using Cu-mediated 18F-fluorination with non-decay-corrected radiochemical yields of 15 ± 6% and 18 ± 2% over 85 and 80 min, respectively, with high radiochemical purities (>97%) and molar activities (140-416 GBq/µmol). In PET imaging studies in rats, both [18F]2 and [18F]9 demonstrated specific binding in CB2-rich spleen after pretreatment with CB2-specific GW405833. Moreover, [18F]9 exhibited higher brain uptake at later time points in a murine model of neuroinflammation compared with a healthy control group. The results suggest further evaluation of azaindole based CB2 radioligands is warranted in other neuroinflammation models.

Spiky Silver-Iron Oxide Nanohybrid for Effective Dual-Imaging and Synergistic Thermo-Chemotherapy.

Nanophotothermal therapy based on nanoparticles (NPs) that convert near-infrared (NIR) light to generate heat to selectively kill cancer cells has attracted immense interest due to its high efficacy and being free of ionizing radiation damage. Here, for the first time, we have designed a novel nanohybrid, silver-iron oxide NP (AgIONP), which was successfully tuned for strong absorbance at NIR wavelengths to be effective in photothermal treatment and dual-imaging strategy using MRI and photoacoustic imaging (PAI) in a cancer model in vivo and in vitro, respectively. We strategically combine the inherent anticancer activity of silver and photothermal therapy to render excellent therapeutic capability of AgIONPs. In vitro phantoms and in vivo imaging studies displayed preferential uptake of folate-targeted NPs in a cancer mice model, indicating the selective targeting efficiency of NPs. Importantly, a single intravenous injection of NPs in a cancer mice model resulted in significant tumor reduction, and photothermal laser resulted in a further substantial synergistic decrease in tumor size. Additionally, biosafety and biochemical assessment performed in mice displayed no significant difference between NP treatment and control groups. Overall, our folic acid AgIONPs displayed excellent potential in the simultaneous application for safe and successful targeted synergistic photothermal treatment and imaging of a cancer model.

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid α/ß-Hydrolase Domain 6 (ABHD6).

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid α/ß-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.

In vivo imaging and biodistribution of multimodal polymeric nanoparticles delivered to the optic nerve.

The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or disease in the central nervous system (CNS) holds great promise. However, the biodistribution of nanoparticles following in vivo administration is often unknown, and concerns have been raised regarding potential toxicity. Using poly(glycidyl methacrylate) (PGMA) nanoparticles coated with polyethylenimine (PEI) and containing superparamagnetic iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent and rhodamine B as a fluorophore, whole animal MRI and fluorescence analyses are used to demonstrate that these nanoparticles (NP) remain close to the site of injection into a partial injury of the optic nerve, a CNS white matter tract. In addition, some of these NP enter axons and are transported to parent neuronal somata. NP also remain in the eye following intravitreal injection, a non-injury model. Considerable infiltration of activated microglia/macrophages occurs in both models. Using magnetic concentration and fluorescence visualization of tissue homogenates, no dissemination of the NP into peripheral tissues is observed. Histopathological analysis reveals no toxicity in organs other than at the injection sites. Multifunctional nanoparticles may be a useful mechanism to deliver therapeutic agents to the injury site and somata of injured CNS neurons and thus may be of therapeutic value following brain or spinal cord trauma.

Microscopic diffusion anisotropy in formalin fixed prostate tissue: preliminary findings.

Diffusion tensor microimaging at 16.4 T with 40 µm isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.47-0.66) significantly higher (P < 0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.31-0.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo.