Targeted inhibition of autophagy in hepatic stellate cells by hydroxychloroquine: An effective therapeutic approach for the treatment of liver fibrosis.

BACKGROUND AND PURPOSE: Liver fibrosis is a wound-healing reaction which is the main cause of chronic liver diseases worldwide. The activated hepatic stellate cell (aHSC) is the main driving factor in the development of liver fibrosis. Inhibiting autophagy of aHSC can prevent the progression of liver fibrosis, but inhibiting autophagy of other liver cells has opposite effects. Hence, targeted inhibition of autophagy in aHSC is quite necessary for the treatment of liver fibrosis, which prompts us to explore the targeted delivery system of small molecule autophagy inhibitor hydroxychloroquine (HCQ) that can target aHSC and alleviate the liver fibrosis. METHODS: The delivery system of HCQ@retinol-liposome nanoparticles (HCQ@ROL-LNPs) targeting aHSC was constructed by the film dispersion and pH-gradient method. TGF-ß-induced HSC activation and thioacetamide (TAA)-induced liver fibrosis mice model were established, and the targeting ability and therapeutic effect of HCQ@ROL-LNPs in liver fibrosis were studied subsequently in vitro and in vivo. RESULTS: HCQ@ROL-LNPs have good homogeneity and stability. They inhibited the autophagy of aHSC selectively by HCQ and reduced the deposition of extracellular matrix (ECM) and the damage to other liver cells. Compared with the free HCQ and HCQ@LNPs, HCQ@ROL-LNPs had good targeting ability, showing enhanced therapeutic effect and low toxicity to other organs. CONCLUSION: Construction of HCQ@ROL-LNPs delivery system lays a theoretical and experimental foundation for the treatment of liver fibrosis and promotes the development of clinical therapeutic drugs for liver diseases.

Processed Polygonatum cyrtonema Hua attenuates postpartum depression in rat model by regulating monoamines and hormones.

Background: Polygonatum cyrtonema Hua is a traditional Chinese medicinal food herb which can regulate the liver and Qi, nourish the heart and blood, moisten the lungs and nourish the kidneys with the potential to treat emotional diseases. However, few studies have explored the effects of Polygonatum cyrtonema Hua on postpartum depression. Therefore, we investigated whether processed Polygonatum cyrtonema Hua could improve postpartum depression in rat models by regulating monoamines and hormones. Methods: Female Sprague-Dawley rats were randomized into normal control (0.9%Nacl), Sham operation (0.9%Nacl), postpartum depression model (0.9%Nacl), fluoxetine (2.5 mg/kg Fluoxetine), low, medium and high dose of processed Polygonatum cyrtonema Hua (2.5 g/kg, 5 g/kg, 10 g/kg) groups. Rats in these groups received drug intervention, and then subjected to Open-field test and Forced swimming test. Brain tissues and serum samples were collected and used to quantify levels of monoamines, hypothalamic-pituitary-adrenal axis and serum Estradiol. The status of neuronal cells in hippocampus 1 region was examined through hematoxylin-eosin staining, whereas expression of estrogen receptor α and ß was detected by immunohistochemistry. Results: Rats in the model group showed decreased mobility time, the disorder of neuronal cells in hippocampus 1 area, and decreased concentration of 5-hydroxytryptamine and dopamine in brain tissue, norepinephrine and estradiol in serum as well as estrogen receptor α and ß expression. They also exhibited increased adrenocorticotropic hormone, corticosterone and corticotropin releasing hormone in serum. However, the treatment with processed Polygonatum cyrtonem Hua or fluoxetine reversed the above abnormalities. Conclusion: The H group showed significant improvement in postpartum depression in rats, and processed Polygonatum cyrtonema Hua can be used as a developing drug for the prevention or treatment of depression.

Effects of atropine eyedrops at ten different concentrations for myopia control in children: A systematic review on meta-analysis.

PURPOSE: To estimate the effect of atropine eyedrops at different concentrations for myopia control in children. METHODS: We conducted a Bayesian random-effects network meta-analysis based on randomized controlled trials (RCT). Primary outcomes include changes in spherical equivalent error (SER) and changes in axial length (AL), mean difference (MD) together with 95% credible interval (CrI) were used to evaluate the efficacy. RESULTS: 28 RCTs (6608 children) were included in this review. Comparing ten atropine eyedrops (0.0025%, 0.005%, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.25%, 0.5% and 1% concentrations) with the placebo, the MDs and 95%CrIs of changes in SER are -0.006 (-0.269, 0.256) D, 0.216 (-0.078, 0.508) D, 0.146 (0.094, 0.199) D, 0.167 (0.039, 0.297) D, 0.201 (0.064, 0.341) D, 0.344 (0.251, 0.440) D, 0.255 (0.114, 0.396) D, 0.296 (0.140, 0.452) D, 0.331 (0.215, 0.447) D, and 0.286 (0.195, 0.337) D, respectively. The MDs and 95%CrIs of changes in AL are -0.048 (-0.182, 0.085) mm, -0.078 (-0.222, 0.066) mm, -0.095 (-0.130, -0.060) mm, -0.096 (-0.183, -0.009) mm, -0.083 (-0.164, -0.004) mm, -0.114 (-0.176, -0.056) mm, -0.134 (-0.198, -0.032) mm, -0.174 (-0.315, -0.061) mm, -0.184 (-0.291, -0.073) mm, and -0.171 (-0.203, -0.097) mm, respectively.Whether evaluated by SER or AL, 1% concentration ranks first in efficacy, but the risk of photophobia is 17 times higher than 0.01% concentration. CONCLUSIONS: 0.01% or higher concentration atropine eyedrops are effective for myopia control, while 0.0025% and 0.005% concentrations may not. As the concentration increases, the effect tends to increase, 1% concentration may have the strongest effect.

Quantitative 17 O MRSI of myocardial oxygen metabolic rate, blood flow, and oxygen extraction fraction under normal and high workload conditions.

PURPOSE: The heart is a highly aerobic organ consuming most of the oxygen the body in supporting heart function. Quantitative imaging of myocardial oxygen metabolism and perfusion is essential for studying cardiac physiopathology in vivo. Here, we report a new imaging method that can simultaneously assess myocardial oxygen metabolism and blood flow in the rat heart. METHODS: This novel method is based on the 17 O-MRSI combined with brief inhalation of 17 O-isotope labeled oxygen gas for quantitative imaging of myocardial metabolic rate of oxygen consumption (MVO2 ), myocardial blood flow (MBF), and oxygen extraction fraction (OEF). We demonstrate this imaging method under basal and high workload conditions in rat hearts at 9.4 T. RESULTS: We show that this 17 O MRSI-based approach can directly measure and image MVO2 (1.35-4.06 µmol/g/min), MBF (0.49-1.38 mL/g/min), and OEF (0.33-0.44) in the heart of anesthetized rat under basal and high workload (21.6 × 103 -56.7 × 103 mmHg • bpm) conditions. Under high workload condition, MVO2 and MBF values in healthy rats approximately doubled, whereas OEF remained unchanged, indicating a strong coupling between myocardial oxygen metabolic demand and supply through blood perfusion. CONCLUSION: The 17 O-MRSI method has been used to simultaneously image the myocardial metabolic rate of oxygen consumption, blood flow, and oxygen extraction fraction in small animal hearts, which are sensitive to the physiological changes induced by high workload. This approach could provide comprehensive measures that are critical for studying myocardial function in normal and diseased states and has a potential for translation.

Mapping brain networks in MPS I mice and their restoration following gene therapy.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.

Dual-frequency resonant coil design for low-γ X-nuclear and proton magnetic resonance imaging at ultrahigh fields.

Low-γ X-nuclear MRS and imaging have played a key role in studying metabolism and physiopathology, especially at ultrahigh fields. We design and demonstrate a novel and simple dual-frequency RF resonant coil that can operate at both low-γ X-nuclear and proton frequencies. The dual-frequency resonant coil comprises an LC coil loop and a tuning-matching circuit bridged by two short wires of the desired length to generate two resonant modes: one for proton MRI and the other for low-γ X-nuclear MRS imaging with a large difference in their Larmor frequencies at ultrahigh fields. The coil parameters for the desired coil size and resonant frequencies can be determined via numerical simulations based on LC circuit theory. We designed, constructed, and evaluated several prototype surface coils and quadrature array coils for 1 H and 2 H or 17 O imaging, with small-sized (diameter ≤ 5 cm) coils evaluated using a 16.4 T animal scanner, and a large-sized (15 cm diameter) coil on a 7 T human scanner. All coils could be tuned/matched and driven in the single coil or array coil mode to the resonant frequencies of 1 H (698 and 298 MHz), 2 H (107 and 45.8 MHz), or 17 O (94.7 and 40.4 MHz) for imaging measurements and evaluation at 16.4 and 7 T, respectively. The dual-frequency resonant coil or array provides adequate detection sensitivity for 1 H MRI and excellent performance for low-γ X-nuclear MRS imaging applications, and excellent coil decoupling efficiency between the array coils at both resonant frequencies with an optimal geometric overlap. It provides a simple, cost-effective dual-frequency RF coil solution to perform low-γ X-nuclear MRS imaging for preclinical and human applications, especially at ultrahigh fields.

Deep Transfer Learning-Based Multi-Object Detection for Plant Stomata Phenotypic Traits Intelligent Recognition.

Plant stomata phenotypic traits can provide a basis for enhancing crop tolerance in adversity. Manually counting the number of stomata and measuring the height and width of stomata obviously cannot satisfy the high-throughput data. How to detect and recognize plant stomata quickly and accurately is the prerequisite and key for studying the physiological characteristics of stomata. In this research, we consider stomata recognition as a multi-object detection problem, and propose an end-to-end framework for intelligent detection and recognition of plant stomata based on feature weights transfer learning and YOLOv4 network. It is easy to operate and greatly facilitates the analysis of stomata phenotypic traits in high-throughput plant epidermal cell images. For different cultivars, multi-scales, rich background features, high density, and small stomata object images, the proposed method can precisely locate multiple stomata in microscope images and automatically give phenotypic traits of stomata. Users can also adjust the corresponding parameters to maximize the accuracy and scalability of automatic stomata detection and recognition. Experimental results on actual data provided by the National Maize Improvement Center show that the proposed method is superior to the existing methods in high stomata automatic detection and recognition accuracy, low training cost, strong generalization ability.

Denoise Functional Magnetic Resonance Imaging With Random Matrix Theory Based Principal Component Analysis.

High-resolution functional MRI (fMRI) is largely hindered by random thermal noise. Random matrix theory (RMT)-based principal component analysis (PCA) is promising to reduce such noise in fMRI data. However, there is no consensus about the optimal strategy and practice in implementation. In this work, we propose a comprehensive RMT-based denoising method that consists of 1) rank and noise estimation based on a set of newly derived multiple criteria, and 2) optimal singular value shrinkage, with each module explained and implemented based on the RMT. By incorporating the variance stabilizing approach, the denoising method can deal with low signal-to-noise ratio (SNR) (such as <5) magnitude fMRI data with favorable performance compared to other state-of-the-art methods. Results from both simulation and in-vivo high-resolution fMRI data show that the proposed denoising method dramatically improves image restoration quality, promoting functional sensitivity at the same level of functional mapping blurring compared to existing denoising methods. Moreover, the denoising method can serve as a drop-in step in data preprocessing pipelines along with other procedures aimed at removal of structured physiological noises. We expect that the proposed denoising method will play an important role in leveraging high-quality, high-resolution task fMRI, which is desirable in many neuroscience and clinical applications.

Toward Completely Sampled Extracellular Neural Recording During fMRI.

This work aims to estimate severe fMRI scanning artifacts in extracellular neural recordings made at ultrahigh magnetic field strengths in order to remove the artifact interferences and uncover the complete neural electrophysiology signal. We build on previous work that used PCA to denoise EEG recorded during fMRI, adapting it to cover the much larger frequency range (1-6000 Hz) of the extracellular field potentials (EFPs) observed by extracellular neural recordings. We examine the singular value decomposition (SVD)-PCA singular value shrinkage (SVS) and compare two shrinkage rules and a sliding template subtraction approach. Additionally, we present a new technique for estimating the singular value upper bounds in spontaneous neural activity recorded in the isoflurane anesthetized rat that uses the temporal first difference of the neural signal. The approaches are tested on artificial datasets to examine their efficacy in detecting extracellular action potentials (EAPs: 300-6000 Hz) recorded during fMRI gradient interferences. Our results indicate that it is possible to uncover the EAPs recorded during gradient interferences. The methods are then tested on natural (non-artificial) datasets recorded from the cortex of isoflurane anesthetized rats, where both local field potential (LFP: 1-300 Hz) and EAP signals are analyzed. The SVS methods are shown to be advantageous compared to sliding template subtraction, especially in the high frequency range corresponding to EAPs. Our novel approach moves us towards simultaneous fMRI and completely sampled neural recording (1-6000Hz with no temporal gaps), providing the opportunity for further study of spontaneous brain function and neurovascular coupling at ultrahigh field in the isoflurane anesthetized rat.

Cortical layer-specific differences in stimulus selectivity revealed with high-field fMRI and single-vessel resolution optical imaging of the primary visual cortex.

The mammalian neocortex exhibits a stereotypical laminar organization, with feedforward inputs arriving primarily into layer 4, local computations shaping response selectivity in layers 2/3, and outputs to other brain areas emanating via layers 2/3, 5 and 6. It cannot be assumed a priori that these signatures of laminar differences in neuronal circuitry are reflected in hemodynamic signals that form the basis of functional magnetic resonance imaging (fMRI). Indeed, optical imaging of single-vessel functional responses has highlighted the potential limits of using vascular signals as surrogates for mapping the selectivity of neural responses. Therefore, before fMRI can be employed as an effective tool for studying critical aspects of laminar processing, validation with single-vessel resolution is needed. The primary visual cortex (V1) in cats, with its precise neuronal functional micro-architecture, offers an ideal model system to examine laminar differences in stimulus selectivity across imaging modalities. Here we used cerebral blood volume weighted (wCBV) fMRI to examine if layer-specific orientation-selective responses could be detected in cat V1. We found orientation preference maps organized tangential to the cortical surface that typically extended across depth in a columnar fashion. We then examined arterial dilation and blood velocity responses to identical visual stimuli by using two- and three- photon optical imaging at single-vessel resolution-which provides a measure of the hemodynamic signals with the highest spatial resolution. Both fMRI and optical imaging revealed a consistent laminar response pattern in which orientation selectivity in cortical layer 4 was significantly lower compared to layer 2/3. This systematic change in selectivity across cortical layers has a clear underpinning in neural circuitry, particularly when comparing layer 4 to other cortical layers.

Reference-Free Adaptive Filtering of Extracellular Neural Signals Recording in Ultra-High Field Magnetic Resonance Imaging Scanners: Removal of Periodic Interferences.

This paper focuses on the removal of periodic artifacts from neural signals recorded in rats in ultra-high field (UHF) MRI scanners, using a reference free adaptive feedforward method. Recording extracellular neural signals in the UHF environment is motivated by the desire to combine neural recording and UHF functional magnetic resonance imaging (fMRI) to better understand brain function. However, the neural signals are found to have extremely high noise artifacts of a periodic nature due to electromagnetic interference and due to small oscillatory motions. In particular, noise at 60 Hz and several harmonics of 60 Hz, sinusoidal noise from a pump, and low frequency breathing motion artifacts are observed. Due to significant overlap between the noise frequencies and the neural frequency region of interest, band pass filters cannot be effectively utilized in this application. Hence, this paper develops adaptive least squares feedforward cancellation filters to remove the periodic artifacts. The interference fundamental frequency is identified precisely using an implementation of k-means in an iterative approach. The paper includes significant animal data from rats recorded in an IACUC-approved procedure in 9.4T and 16.4T MRI machines. For breathing artifacts filtered from 4 rats, the mean signal cancellation values at the harmonic interference frequencies are 5.18, 12.97, and 20.87 dB/Hz for a sliding template subtraction, a single-stage impulse reference method, and the cascaded adaptive filtering approach respectively. For pump artifacts filtered from 2 chronically implanted rats, mean signal cancellation values are 2.85, 9.52 and 12.06 dB/Hz respectively. The experimental results show that periodic noise is very effectively removed by the developed cascaded adaptive least squares feedforward algorithm.

Effect of JAK inhibitors on high- and low-density lipoprotein in patients with rheumatoid arthritis: a systematic review and network meta-analysis.

OBJECTIVES: Janus kinase (JAK) inhibitors are a new class of medication for treatment of rheumatoid arthritis (RA), and such inhibitors alter levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in RA patients. However, the extent of such changes has not been systematically reviewed. METHOD: A systematic review and network meta-analysis was performed on randomized trials in RA patients in response to JAKi identified from Pubmed, Medline, Embase, and Cochrane Controlled Trials Register. The primary outcome was mean change of HDL-C and LDL-C from baseline. Mean treatment differences and the rank of the effect of various JAKi on HDL-C and LDL-C were estimated. RESULTS: Based on data from 18 unique studies involving five approved JAK inhibitors and 6697 RA patients (JAKi = 3341, placebo = 3356), such inhibitors led to a mean increase of 8.11 mg/dl (95% CI 6.65-9.58, I2 = 82%) in HDL levels from baseline, and a mean increase of 11.37 mg/dl (95% CI 7.84-14.91, I2 = 88%) in LDL levels from baseline. Cardiovascular disease risk did not differ significantly between patients who received JAK inhibitors or those who received placebo or active agents. CONCLUSIONS: Our analysis suggests that, at their recommended doses, all five JAK inhibitors lead to an increase in HDL and LDL levels in RA patients. Further long-term research is required to extend these results and understand whether changes in lipid levels in RA patients can affect cardiovascular risk. Key Points • This is the first systematic review and NMA examining the effect of all five clinically approved JAK inhibitors on lipid levels in RA patients. • Recommended doses of JAK inhibitors used for the treatment of RA patients can induce a significant increase in HDL and LDL levels. • Indirect pairwise comparisons suggest that only upadacitinib and peficitinib have significantly different ability to induce LDL change in RA patients.

Machine Learning-Enabled High-Resolution Dynamic Deuterium MR Spectroscopic Imaging.

Deuterium magnetic resonance spectroscopic imaging (DMRSI) has recently been recognized as a potentially powerful tool for noninvasive imaging of brain energy metabolism and tumor. However, the low sensitivity of DMRSI has significantly limited its utility for both research and clinical applications. This work presents a novel machine learning-based method to address this limitation. The proposed method synergistically integrates physics-based subspace modeling and data-driven deep learning for effective denoising, making high-resolution dynamic DMRSI possible. Specifically, a novel subspace model was used to represent the dynamic DMRSI signals; deep neural networks were trained to capture the low-dimensional manifolds of the spectral and temporal distributions of practical dynamic DMRSI data. The learned subspace and manifold structures were integrated via a regularization formulation to remove measurement noise. Theoretical analysis, computer simulations, and in vivo experiments have been conducted to demonstrate the denoising efficacy of the proposed method which enabled high-resolution imaging capability. The translational potential was demonstrated in tumor-bearing rats, where the Warburg effect associated with cancer metabolism and tumor heterogeneity were successfully captured. The new method may not only provide an effective tool to enhance the sensitivity of DMRSI for basic research and clinical applications but also provide a framework for denoising other spatiospectral data.

Noninvasive assessment of myocardial energy metabolism and dynamics using in vivo deuterium MRS imaging.

PURPOSE: The assessment of cellular energy metabolism is crucial for understanding myocardial physiopathology. Here, we conducted a pilot study to develop an alternative imaging approach for the assessment of myocardial energy metabolism. METHODS: We developed a deuterium MRSI method to noninvasively monitor the accumulation of deuterated downstream metabolites and deuterated water in rat hearts infused with deuterated glucose or acetate substrate on a 16.4 Tesla animal scanner. RESULTS: We found that the deuterated water accumulation rate and isotopic turnover rate of deuterated glutamate/glutamine via the tricarboxylic acid cycle and exchange in rat hearts were much higher when infused with acetate compared to that with glucose, demonstrating the myocardium substrate preference for acetate over glucose. CONCLUSION: We demonstrated the feasibility of deuterium MRSI for noninvasive imaging and assessment of myocardial energy metabolism in vivo. Although the strong signal and large dynamics of myocardial deuterated water may provide a sensitive imaging biomarker, quantifying the metabolic rates still poses a challenge due to the confounding effects of blood recirculation, perfusion, and multiple deuterated water production pathways. In contrast, the deuterated glutamate/glutamine signal and change should directly reflect the metabolic activity of the myocardial tricarboxylic acid cycle, which can be used to study the metabolic shift in substance preference between acetate and glucose in the diseased state. Deuterium MRSI is noninvasive and robust and may have the potential to assess myocardial energy metabolism in human patients.

Novel Composite Gold-Aluminum Electrode with Application to Neural Recording and Stimulation in Ultrahigh Field Magnetic Resonance Imaging Scanners.

Traditional electrodes used for neural recording and stimulation generate large regions of signal void (no functional MRI signal) when used in ultrahigh field (UHF) MRI scanners. This is a significant disadvantage when simultaneous neural recording/stimulation and fMRI signal acquisition is desired, for example in understanding the functional mechanisms of deep brain stimulation (DBS). In this work, a novel gold-aluminum microwire neural electrode is presented which overcomes this disadvantage. The gold-aluminum design greatly reduces the magnetic susceptibility difference between the electrode and brain tissue leading to significantly reduced regions of signal void. Gold-aluminum microwire samples are imaged at ultrahigh field 16.4 Tesla and compared with gold-only and aluminum-only microwire samples. First, B0 field mapping was used to quantify field distortions at 16.4T and compared with analytical computations in an agarose phantom. The gold-aluminum microwire samples generated substantially less field distortion and signal loss in comparison with gold-only and aluminum-only samples at 16.4T using gradient echo imaging and echo planar imaging sequences. Next, the proposed gold-aluminum electrode was used to successfully record local field potential signals from a rat cortex. The newly proposed gold-aluminum microwire electrode exhibits reduced field distortions and signal loss at 16.4T, a finding which translates to MRI scanners of lower magnetic field strengths as well. The design can be easily reproduced for widespread study of DBS using MRI in animal models. Additionally, the use of non-reactive gold and aluminum materials presents an avenue for translation to human implant applications in the future.

The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial.

CONTEXT: Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. OBJECTIVE: To observe the clinical safety and tolerability of CALAS. MATERIALS AND METHODS: Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. RESULTS: Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). DISCUSSION AND CONCLUSIONS: CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

Quantitative Assessment of Occipital Metabolic and Energetic Changes in Parkinson's Patients, Using In Vivo 31P MRS-Based Metabolic Imaging at 7T.

Abnormal energy metabolism associated with mitochondrial dysfunction is thought to be a major contributor to the progression of neurodegenerative diseases such as Parkinson's disease (PD). Recent advancements in the field of magnetic resonance (MR) based metabolic imaging provide state-of-the-art technologies for non-invasively probing cerebral energy metabolism under various brain conditions. In this proof-of-principle clinical study, we employed quantitative 31P MR spectroscopy (MRS) imaging techniques to determine a constellation of metabolic and bioenergetic parameters, including cerebral adenosine triphosphate (ATP) and other phosphorous metabolite concentrations, intracellular pH and nicotinamide adenine dinucleotide (NAD) redox ratio, and ATP production rates in the occipital lobe of cognitive-normal PD patients, and then we compared them with age-sex matched healthy controls. Small but statistically significant differences in intracellular pH, NAD and ATP contents and ATPase enzyme activity between the two groups were detected, suggesting that subtle defects in energy metabolism and mitochondrial function are quantifiable before regional neurological deficits or pathogenesis begin to occur in these patients. Pilot data aiming to evaluate the bioenergetic effect of mitochondrial-protective bile acid, ursodeoxycholic acid (UDCA) were also obtained. These results collectively demonstrated that in vivo 31P MRS-based neuroimaging can non-invasively and quantitatively assess key metabolic-energetic metrics in the human brain. This provides an exciting opportunity to better understand neurodegenerative diseases, their progression and response to treatment.

Quantitative and simultaneous measurement of oxygen consumption rates in rat brain and skeletal muscle using 17 O MRS imaging at 16.4T.

PURPOSE: Oxygen-17 (17 O) MRS imaging, successfully used in the brain, is extended by imaging the oxygen metabolic rate in the resting skeletal muscle and used to determine the total whole-body oxygen metabolic rate in the rat. METHODS: During and after inhalations of 17 O2 gas, dynamic 17 O MRSI was performed in rats (n = 8) ventilated with N2 O or N2 at 16.4 T. Time courses of the H217 O concentration from regions of interest located in brain and muscle tissue were examined and used to fit an animal-adapted 3-phase metabolic model of oxygen consumption. CBF was determined with an independent washout method. Finally, body oxygen metabolic rate was calculated using a global steady-state approach. RESULTS: Cerebral metabolic rate of oxygen consumption was 1.97 ± 0.19 µmol/g/min on average. The resting metabolic rate of oxygen consumption in skeletal muscle was 0.32 ± 0.12 µmol/g/min and >6 times lower than cerebral metabolic rate of oxygen consumption. Global oxygen consumed by the body was 24.2 ± 3.6 mL O2 /kg body weight/min. CBF was estimated to be 0.28 ± 0.02 mL/g/min and 0.34 ± 0.06 mL/g/min for the N2 and N2 O ventilation condition, respectively. CONCLUSION: We have evaluated the feasibility of 17 O MRSI for imaging and quantifying the oxygen consumption rate in low metabolizing organs such as the skeletal muscle at rest. Additionally, we have shown that CBF is slightly increased in the case of ventilation with N2 O. We expect this study to be beneficial to the application of 17 O MRSI to a wider range of organs, although further validation is advised.