Functional assessment of strains around a full-thickness and critical sized articular cartilage defect under compressive loading using MRI.

OBJECTIVE: The objective of this study was to evaluate the effect of full-thickness chondral defects on intratissue deformation patterns and matrix constituents in an experimental model mimicking in vivo cartilage-on-cartilage contact conditions. DESIGN: Pairs of bovine osteochondral explants, in a unique cartilage-on-cartilage model system, were compressed uniaxially by 350 N during 2 s loading and 1.4 s unloading cycles (≈1700 repetitions). Tissue deformations under quasi-steady state load deformation response were measured with displacement encoded imaging with stimulated echoes (DENSE) in a 9.4 T magnetic resonance imaging (MRI) scanner. Pre- and post-loading, T1, T2 and T1ρ relaxation time maps were measured. We analyzed differences in strain patterns and relaxation times between intact cartilage (n = 8) and cartilage in which a full-thickness and critical sized defect was created (n = 8). RESULTS: Under compressive loading, strain magnitudes were elevated at the defect rim, with elevated tensile and compressive principal strains (Δϵmax = 4.2%, P = 0.02; Δϵmin = -4.3%, P = 0.02) and maximum shear strain at the defect rim (Δγmax = 4.4%, P = 0.007). The opposing cartilage showed minimal increase in strain patterns at contact with the defect rim but decreased strains opposing the defect. After defect creation, T1, T2 and T1ρ relaxation times were elevated at the defect rim only. Following loading, the overall relaxations times of the defect tissue and especially at the rim, increased compared to intact cartilage. CONCLUSIONS: This study demonstrates that the local biomechanical changes occurring after defect creation may induce tissue damage by increasing shear strains and depletion of cartilage constituents at the defect rim under compressive loading.

Cartilage-on-cartilage contact: effect of compressive loading on tissue deformations and structural integrity of bovine articular cartilage.

OBJECTIVE: This study aims to characterize the deformations in articular cartilage under compressive loading and link these to changes in the extracellular matrix constituents described by magnetic resonance imaging (MRI) relaxation times in an experimental model mimicking in vivo cartilage-on-cartilage contact. DESIGN: Quantitative MRI images, T1, T2 and T1ρ relaxation times, were acquired at 9.4T from bovine femoral osteochondral explants before and immediately after loading. Two-dimensional intra-tissue displacement and strain fields under cyclic compressive loading (350N) were measured using the displacement encoding with stimulated echoes (DENSE) method. Changes in relaxation times in response to loading were evaluated against the deformation fields. RESULTS: Deformation fields showed consistent patterns among all specimens, with maximal strains at the articular surface that decrease with tissue depth. Axial and transverse strains were maximal around the center of the contact region, whereas shear strains were minimal around the contact center but increased towards contact edges. A decrease in T2 and T1ρ was observed immediately after loading whereas the opposite was observed for T1. No correlations between cartilage deformation patterns and changes in relaxation times were observed. CONCLUSIONS: Displacement encoding combined with relaxometry by MRI can noninvasively monitor the cartilage biomechanical and biochemical properties associated with loading. The deformation fields reveal complex patterns reflecting the depth-dependent mechanical properties, but intra-tissue deformation under compressive loading does not correlate with structural and compositional changes. The compacting effect of cyclic compression on the cartilage tissue was revealed by the change in relaxation time immediately after loading.

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome.

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

Multimodal assessment of early tumor response to chemotherapy: comparison between diffusion-weighted MRI, 1H-MR spectroscopy of choline and USPIO particles targeted at cell death.

The aim of this study was to determine the value of different magnetic resonance (MR) protocols to assess early tumor response to chemotherapy. We used a murine tumor model (TLT) presenting different degrees of response to three different cytotoxic agents. As shown in survival curves, cyclophosphamide (CP) was the most efficient drug followed by 5-fluorouracil (5-FU), whereas the etoposide treatment had little impact on TLT tumors. Three different MR protocols were used at 9.4 Tesla 24 h post-treatment: diffusion-weighted (DW)-MRI, choline measurement by (1) H MRS, and contrast-enhanced MRI using ultrasmall iron oxide nanoparticles (USPIO) targeted at phosphatidylserine. Accumulation of contrast agent in apoptotic tumors was monitored by T(2) -weighted images and quantified by EPR spectroscopy. Necrosis and apoptosis were assessed by histology. Large variations were observed in the measurement of choline peak areas and could not be directly correlated to tumor response. Although the targeted USPIO particles were able to significantly differentiate between the efficiency of each cytotoxic agent and best correlated with survival endpoint, they present the main disadvantage of non-specific tumor accumulation, which could be problematic when transferring the method to the clinic. DW-MRI presents a better compromise by combining longitudinal studies with a high dynamic range; however, DW-MRI was unable to show any significant effect for 5-FU. This study illustrates the need for multimodal imaging in assessing tumor response to treatment to compensate for individual limitations.

Effect of gelatinase inhibition on adipogenesis and adipose tissue development.

1. The potential of the matrix metalloproteinase (MMP) inhibitor ABT-518 to affect pre-adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using mouse models of adipogenesis and obesity. 2. Differentiation of 3T3-F442A pre-adipocytes into mature adipocytes was enhanced in a dose-dependent manner by the addition of ABT-518 (0-100 µmol/L). This was associated with increased expression of the adipogenic markers adipocyte fatty acid-binding protein 2 (AP2), peroxisome proliferator-activated receptor γ and adiponectin. 3. Feeding 5-week-old male wild-type mice with a high-fat diet, with or without ABT-518 (to achieve a dose of 100 mg/kg per day), for 16 weeks resulted in a significant reduction in bodyweight throughout the experimental period. Magnetic resonance spectroscopy revealed that the lipid : water ratio was significantly lower in ABT-518-treated mice. The total weight of isolated subcutaneous or gonadal fat depots did not differ significantly following ABT-518 treatment, but adipocyte and blood vessel size were significantly reduced in the gonadal fat. 4. Administration of ABT-518-2 (100 mg/kg per day for 10 weeks) to 5-week-old male wild-type mice with established obesity maintained on a high-fat diet had no effect on total bodyweight at the end of the experiment, but was associated with reduced blood vessel size in the fat depots. 5. Thus, the MMP inhibitor ABT-518 stimulates differentiation of 3T3-F442A pre-adipocytes in vitro. It mildly reduces bodyweight gain in a murine model of diet-induced obesity, but does not affect established obesity.

Evaluation of the specificity and sensitivity of ferritin as an MRI reporter gene in the mouse brain using lentiviral and adeno-associated viral vectors.

The development of in vivo imaging protocols to reliably track transplanted cells or to report on gene expression is critical for treatment monitoring in (pre)clinical cell and gene therapy protocols. Therefore, we evaluated the potential of lentiviral vectors (LVs) and adeno-associated viral vectors (AAVs) to express the magnetic resonance imaging (MRI) reporter gene ferritin in the rodent brain. First, we compared the induction of background MRI contrast for both vector systems in immune-deficient and immune-competent mice. LV injection resulted in hypointense (that is, dark) changes of T(2)/T(2)(*) (spin-spin relaxation time)-weighted MRI contrast at the injection site, which can be partially explained by an inflammatory response against the vector injection. In contrast to LVs, AAV injection resulted in reduced background contrast. Moreover, AAV-mediated ferritin overexpression resulted in significantly enhanced contrast to background on T(2)(*)-weighted MRI. Although sensitivity associated with the ferritin reporter remains modest, AAVs seem to be the most promising vector system for in vivo MRI reporter gene imaging.

Response of mouse brain perfusion to hypo- and hyperventilation measured by arterial spin labeling.

We aimed to setup a noninvasive and well-controlled methodology for evaluation of the cerebrovascular response in mice (C57BL/6J; 12 weeks). Therefore we applied a normo-, hypo-, and hyperventilation paradigm combined with arterial spin labeling and monitoring of the expired CO(2) (expCO(2)) (n=7) or arterial pCO(2) (apCO(2)) (n=12). Reducing the tidal volume by 25% and the respiratory rate by 20% resulted in hypercapnia (apCO(2) from 33 ± 6 mmHg to 64 ± 16 mmHg). Increasing the respiratory rate by 25% and the tidal volume by 20% decreased apCO(2) to 22 ± 5 mmHg. Cerebral blood flow (CBF) was 82 ± 21, 163 ± 41 and 64 ± 18 mL/100 g/min during normo, hypo-, and hyperventilation, respectively (midbrain). The correlation of apCO(2) and CBF levels resulted in a cerebrovascular response of 2.7 ± 0.3, 2.1 ± 0.3, 2.1 ± 0.3, and 3.7 ± 0.5 mL/100 g/min/mmHg for midbrain, cortex, hippocampus and thalamus, respectively. As expCO(2) levels were correlated with apCO(2) (r(2)=0.86; n=4) and CBF (r(2)=0.67) a cerebrovascular response based on simultaneously recorded CBF and expCO(2) levels could be derived (3.3 ± 0.5, 2.5 ± 0.4, 3.0 ± 0.4, and 4.5 ± 0.6 mL/100 g/min/mmHg; order as above). A cross-over experiment resulted in similar responses. In conclusion, this protocol allows evaluating basal CBF and cerebrovascular response in mice under well-controlled conditions by simply changing ventilator settings and correlating CBF with apCO(2) and/or simultaneously obtained expCO(2).

Motor cortex metabolite alterations in amyotrophic lateral sclerosis assessed in vivo using edited and non-edited magnetic resonance spectroscopy.

Previous MRI and proton spectroscopy (1H-MRS) studies have revealed impaired neuronal integrity and altered neurometabolite concentrations in the motor cortex of patients with amyotrophic lateral sclerosis (ALS). Here, we aim to use MRI with conventional and novel MRS sequences to further investigate neurometabolic changes in the motor cortex of ALS patients and their relation to clinical parameters. We utilized the novel HERMES (Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy) MRS sequence to simultaneously quantify the inhibitory neurotransmitter GABA and antioxidant glutathione in ALS patients (n = 7) and healthy controls (n = 7). In addition, we have also quantified other MRS observable neurometabolites using a conventional point-resolved MR spectroscopy (PRESS) sequence in ALS patients (n = 20) and healthy controls (n = 20). We observed a trend towards decreasing glutathione concentrations in the motor cortex of ALS patients (p = 0.0842). In addition, we detected a 11% decrease in N-acetylaspartate (NAA) (p = 0.025), a 15% increase in glutamate + glutamine (Glx) (p = 0.0084) and a 21% increase in myo-inositol (mIns) (p = 0.0051) concentrations for ALS patients compared to healthy controls. Furthermore, significant positive correlations were found between GABA-NAA (p = 0.0480; Rρ = 0.7875) and NAA-mIns (p = 0.0448; Rρ = -0.4651) levels among the patients. NAA levels in the bulbar-onset patient group were found to be significantly (p = 0.0097) lower compared to the limb-onset group. A strong correlation (p < 0.0001; Rρ = -0,8801) for mIns and a weak correlation (p = 0.0066; Rρ = -0,6673) for Glx was found for the disease progression, measured by declining of the ALS Functional Rating Scale-Revised criteria (ALSFRS-R). Concentrations of mIns and Glx also correlated with disease severity measured by forced vital capacity (FVC). Results suggest that mean neurometabolite concentrations detected in the motor cortex may indicate clinical and pathological changes in ALS.

Non-invasive assessment of disease progression and neuroprotective effects of dietary coconut oil supplementation in the ALS SOD1G93A mouse model: A 1H-magnetic resonance spectroscopic study.

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative disease primarily characterized by progressive degeneration of motor neurons in the motor cortex, brainstem and spinal cord. Due to relatively fast progression of ALS, early diagnosis is essential for possible therapeutic intervention and disease management. To identify potential diagnostic markers, we investigated age-dependent effects of disease onset and progression on regional neurochemistry in the SOD1G93A ALS mouse model using localized in vivo magnetic resonance spectroscopy (MRS). We focused mainly on the brainstem region since brainstem motor nuclei are the primarily affected regions in SOD1G93A mice and ALS patients. In addition, metabolite profiles of the motor cortex were also assessed. In the brainstem, a gradual decrease in creatine levels were detected starting from the pre-symptomatic age of 70 days postpartum. During the early symptomatic phase (day 90), a significant increase in the levels of the inhibitory neurotransmitter γ- aminobutyric acid (GABA) was measured. At later time points, alterations in the form of decreased NAA, glutamate, glutamine and increased myo-inositol were observed. Also, decreased glutamate, NAA and increased taurine levels were seen at late stages in the motor cortex. A proof-of-concept (PoC) study was conducted to assess the effects of coconut oil supplementation in SODG93A mice. The PoC revealed that the coconut oil supplementation together with the regular diet delayed disease symptoms, enhanced motor performance, and prolonged survival in the SOD1G93A mouse model. Furthermore, MRS data showed stable metabolic profile at day 120 in the coconut oil diet group compared to the group receiving a standard diet without coconut oil supplementation. In addition, a positive correlation between survival and the neuronal marker NAA was found. To the best of our knowledge, this is the first study that reports metabolic changes in the brainstem using in vivo MRS and effects of coconut oil supplementation as a prophylactic treatment in SOD1G93A mice.

Nonnegative Canonical Polyadic Decomposition for Tissue-Type Differentiation in Gliomas.

Magnetic resonance spectroscopic imaging (MRSI) reveals chemical information that characterizes different tissue types in brain tumors. Blind source separation techniques are used to extract the tissue-specific profiles and their corresponding distribution from the MRSI data. We focus on automatic detection of the tumor, necrotic and normal brain tissue types by constructing a 3D MRSI tensor from in vivo 2D-MRSI data of individual glioma patients. Nonnegative canonical polyadic decomposition (NCPD) is applied to the MRSI tensor to differentiate various tissue types. An in vivo study shows that NCPD has better performance in identifying tumor and necrotic tissue type in glioma patients compared to previous matrix-based decompositions, such as nonnegative matrix factorization and hierarchical nonnegative matrix factorization.

Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI.

Tumor segmentation is a particularly challenging task in high-grade gliomas (HGGs), as they are among the most heterogeneous tumors in oncology. An accurate delineation of the lesion and its main subcomponents contributes to optimal treatment planning, prognosis and follow-up. Conventional MRI (cMRI) is the imaging modality of choice for manual segmentation, and is also considered in the vast majority of automated segmentation studies. Advanced MRI modalities such as perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI) have already shown their added value in tumor tissue characterization, hence there have been recent suggestions of combining different MRI modalities into a multi-parametric MRI (MP-MRI) approach for brain tumor segmentation. In this paper, we compare the performance of several unsupervised classification methods for HGG segmentation based on MP-MRI data including cMRI, DWI, MRSI and PWI. Two independent MP-MRI datasets with a different acquisition protocol were available from different hospitals. We demonstrate that a hierarchical non-negative matrix factorization variant which was previously introduced for MP-MRI tumor segmentation gives the best performance in terms of mean Dice-scores for the pathologic tissue classes on both datasets.

Tensor based tumor tissue type differentiation using magnetic resonance spectroscopic imaging.

Magnetic resonance spectroscopic imaging (MRSI) has the potential to characterise different tissue types in brain tumors. Blind source separation techniques are used to extract the specific tissue profiles and their corresponding distribution from the MRSI data. A 3-dimensional MRSI tensor is constructed from in vivo 2D-MRSI data of individual tumor patients. Non-negative canonical polyadic decomposition (NCPD) with common factor in mode-1 and mode-2 and l(1) regularization on mode-3 is applied on the MRSI tensor to differentiate various tissue types. Initial in vivo study shows that NCPD has better performance in identifying tumor and necrotic tissue type in high grade glioma patients compared to previous matrix-based decompositions, such as non-negative matrix factorization and hierarchical non-negative matrix factorization.

13C NMR evidence of the failure of human erythrocytes to metabolize ascorbate and dehydroascorbate to lactate.

13C-NMR spectroscopy was used to record time courses of the metabolism of [1-(13)C]-L-ascorbic acid (AA) and [2-(13)C]-L-ascorbic acid and their dehydro-counterparts (DHAA) by human erythrocytes. Under a range of experimental conditions, but most notably in the absence of glucose in the incubation medium, no (13)C-NMR signal for lactate emerged during any of the 5 h time courses. The NMR resonances that did emerge over time were assigned to diketogulonic (DKG) acid and CO(2). Only very minor resonances from degradation products of DKG appeared from samples that contained physiologically high concentrations of DHAA. These results are in contrast with those in a recent report that lactate is derived from AA in human erythrocytes. However, an explanation for this possible artifact is given.

Anguivine and isoanguivine, steroid alkaloid glycosides from Solanum anguivi.

In addition to solamargine, two new steroid alkaloid glycosides, anguivine and isoanguivine, have been isolated from the roots of Solanum anguivi, the structures of which have been elucidated as (25R)-3 beta-[O-alpha-L-rhamnopyranosyl-(1-->2)-O-[beta-D- xylopyranosyl-(1-->3)]-beta-D-glucopyranosyloxy]-22 alpha N-spirosol-5-ene and (25R)-3 beta-[O-alpha-L-rhamnopyranosyl-(1-->2)-O-[beta-D-xylopyranosyl- (1-->3)-beta-D-galactopyranosyloxy]-22 alpha N-spirosol-5-ene.

Unsupervised feature dimension reduction for classification of MR spectra.

We present an unsupervised feature dimension reduction method for the classification of magnetic resonance spectra. The technique preserves spectral information, important for disease profiling. We propose to use this technique as a preprocessing step for computationally demanding wrapper-based feature subset selection. We show that the classification accuracy on an independent test set can be sustained while achieving considerable feature reduction. Our method is applicable to other classification techniques, such as neural networks, support vector machines, etc.

Magnetic resonance imaging of human dental pulp stem cells in vitro and in vivo.

Recent advances in stem cell research have shown the promising nature of mesenchymal stem cells as plausible candidates for cell-based regenerative medicine. Many studies reported the use of human dental pulp stem cells (hDPSCs), which possess self-renewal capacity, high proliferation potential, and the ability to undergo multilineage differentiation. Together with this therapeutic approach, development of effective, noninvasive and nontoxic imaging techniques for visualizing and tracking the cells in vivo is crucial for the evaluation and improvement of stem cell therapy. Magnetic resonance imaging (MRI) is one of the most powerful diagnostic imaging techniques currently available for in vivo diagnosis and has been proposed as the most attractive modality for monitoring stem cell migration. The aim of this study was to investigate the labeling efficiency of hDPSCs using superparamagnetic iron oxide (SPIO) particles in order to allow visualization using in vitro and in vivo MRI without influencing cellular metabolism. MRI and transmission electron microscopy (TEM) showed optimal uptake with low SPIO concentrations of 15 µg/ml in combination with 0.75 µg/ml poly-L-lysine (PLL) resulting in more than 13 pg iron/cell and an in vitro detection limit of 50 labeled cells/µl. Very low SPIO concentrations in the culture medium resulted in extremely high labeling efficiency not reported before. For these conditions, tetrazolium salt assays showed no adverse effects on cell viability. Furthermore, in vivo MRI was performed to detect labeled hDPSCs transplanted into the brain of Rag 2-γ C immune-deficient mice. Transplanted cells did not show any signs of tumorgenecity or teratoma formation during the studied time course. We have reported on a labeling and imaging strategy to visualize human dental pulp stem cells in vivo using MRI. These data provide a solid base to allow cell tracking in future regenerative studies in the brain longitudinally.

Evaluation of manganese uptake and toxicity in mouse brain during continuous MnCl2 administration using osmotic pumps.

Manganese is a vital element and cofactor of many key enzymes, but it is toxic at high levels, causing pronounced disturbances in the mammalian brain. Magnetic resonance imaging (MRI) studies using manganese ions as a paramagnetic contrast agent are often limited by the neurotoxicity of Mn(2+) . In this work, we have explored a new in vivo model to study Mn(2+) uptake, distribution and neurotoxicity in mice by subcutaneous implantation of mini-osmotic pumps delivering MnCl(2) continuously for 21 days. Fractionated injections can reduce the toxicity; however, constant administration at very low doses using osmotic pumps caused a substantial effect on the T(1) contrast in MRI while reducing toxicity. Manganese-enhanced MRI documented fast but reversible Mn(2+) deposition largely in glomerular and mitral cell layers of the olfactory bulb, in the CA3 area of the hippocampus, and in the gray matter of the cerebellum. Mn(2+) accumulated as early as the first days after implantation, with a fast dispersal 9 days after stopping a 12-days Mn(2+) exposure. Prominent Mn(2+) accumulation was also seen in salivary glands and in the endocrine thyroid and posterior pituitary gland. These structures with enhanced Mn(2+) accumulation correlated well with those showing high expression of the secretory pathway Ca(2+) /Mn(2+) -ATPase (SPCA1), i.e. a transporter that could take part in Mn(2+) detoxification. Our new experimental model for continuous low-dosage administration of Mn(2+) is an easy alternative for enhancing Mn(2+) -based contrast in MEMRI studies, and might provide insight into the etiology of neuropathologies resulting from chronic Mn(2+) exposure in vivo.

GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity.

GPR39, which may function as a Zn(2+) sensor, is a member of the G protein-coupled receptor family that also includes the receptor for the hunger hormone ghrelin. The down-regulation of GPR39 mRNA in adipose tissue of obese type 2 diabetic patients suggests that GPR39 may contribute to the pathogenesis of the disease. The present study aimed to investigate the role of GPR39 in the regulation of energy balance and glucose homeostasis in wild-type (GPR39(+/+) ) and GPR39 knockout mice (GPR39(-/-) ) with obesity-related type 2 diabetes. GPR39 mRNA levels in adipose tissue of fasted GPR39(+/+) mice fed a high-fat diet (HFD) for 30 weeks were reduced and correlated positively with blood glucose levels. Body weight, fat percentage and energy intake were increased in the HFD group but did not differ between both genotypes. Within the HFD group, blood glucose levels were lower in GPR39(-/-) than in GPR39(+/+) mice, despite significant reductions in prandial plasma insulin levels. The latter may not be a result of changes in ß-cell hyperplasia because immunohistochemical staining of pancreata of mice on a HFD showed no differences between genotypes. The lower blood glucose levels may involve alterations in insulin sensitivity as revealed by glucose tolerance tests and respiratory quotient measurements that showed a preference of obese GPR39(-/-) mice for the use of carbohydrates as metabolic fuel. The increase in plasma ghrelin levels in GPR39(-/-) mice fed a HFD may contribute to the alterations in glucose homeostasis, whereas changes in gastric emptying or intestinal Zn(2+) absorption are not involved. The results obtained in the present study suggest that GPR39 plays a role in the pathogenesis of obesity-related type 2 diabetes by affecting the regulation of glucose homeostasis.

Metabolic and type 1 cannabinoid receptor imaging of a transgenic rat model in the early phase of Huntington disease.

Several lines of evidence imply early alterations in metabolic and endocannabinoid neurotransmission in Huntington disease (HD). Using [(18)F]MK-9470 and small animal PET, we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding in vivo in pre-symptomatic and early symptomatic rats of HD (tgHD), in relation to glucose metabolism, morphology and behavioral testing for motor and cognitive function. Twenty-three Sprague-Dawley rats (14 tgHD and 9 wild-types) were investigated between the age of 2 and 11 months. Relative glucose metabolism and parametric CB1 receptor images were anatomically standardized to Paxinos space and analyzed voxel-wise. Volumetric microMRI imaging was performed to assess HD neuropathology. Within the first 10 months, bilateral volumes of caudate-putamen and lateral ventricles did not significantly differ between genotypes. Longitudinal- and genotype evolution showed that relative [(18)F]MK-9470 binding progressively decreased in the caudate-putamen and lateral globus pallidus of tgHD rats (-8.3%, p≤1.1×10(-5) at 5 months vs. -10.9%, p<1.5×10(-5) at 10 months). In addition, relative glucose metabolism increased in the bilateral sensorimotor cortex of 2-month-old tgHD rats (+8.1%, p≤1.5×10(-5)), where it was positively correlated to motor function at that time point. TgHD rats developed cognitive deficits at 6 and 11 months of age. Our findings point to early regional dysfunctions in endocannabinoid signalling, involving the lateral globus pallidus and caudate-putamen. In vivo CB1 receptor measurements using [(18)F]MK-9470 may thus be a useful early biomarker for HD. Our results also provide evidence of subtle motor and cognitive deficits at earlier stages than previously described.

In vivo MRI stem cell tracking requires balancing of detection limit and cell viability.

Cell-based therapy using adult mesenchymal stem cells (MSCs) has already been the subject of clinical trials, but for further development and optimization the distribution and integration of the engrafted cells into host tissues have to be monitored. Today, for this purpose magnetic resonance imaging (MRI) is the most suitable technique, and micron-sized iron oxide particles (MPIOs) used for labeling are favorable due to their low detection limit. However, constitutional data concerning labeling efficiency, cell viability, and function are lacking. We demonstrate that cell viability and migratory potential of bone marrow mesenchymal stromal cells (BMSCs) are negatively correlated with incorporated MPIOs, presumably due to interference with the actin cytoskeleton. Nevertheless, labeling of BMSCs with low amounts of MPIOs results in maintained cellular function and sufficient contrast for in vivo observation of single cells by MRI in a rat glioma model. Conclusively, though careful titration is indicated, MPIOs are a promising tool for in vivo cell tracking and evaluation of cell-based therapies.