Detection of Two Different Inner-Sphere Solvent Species in a Eu-Based ParaCEST Agent Dissolved in a Mixture of Methanol and Water: The Impact of Solvents on Exchange Dynamics.

Solvent binding and exchange kinetics are of fundamental importance for lanthanide-based MRI contrast agents, and these properties are critically affected by solvents. In the present work, a water and methanol mixture was used to investigate solvent exchange kinetics in a Eu-DOTA-tetraamide complex by high-resolution H NMR and CEST methods. Two distinct solvated complexes were observed by NMR, one complex capped by a single water molecule and the other by a single methanol molecule.

The Functional Characterization of Venous Thromboembolic Disease (FUVID) study: rationale, design, and methods of a prospective, observational, multicenter study to evaluate mechanisms of exercise intolerance and dyspnea following pediatric pulmonary embolism.

Background: To date, the focus of investigation in pediatric pulmonary embolism (PE) has been on PE recurrence and anticoagulant-related bleeding. While highly relevant, these outcomes do not fully capture functional limitations and the psychological impact that comprises post-PE syndrome.

Objectives: The primary objective of the Functional Characterization of Venous Thromboembolic Disease (FUVID) study was to investigate mechanisms of post-PE syndrome in children.

A 7T MRI Study of Fibular Bone Thickness and Density: Impact of Age, Sex and Body Weight, and Correlation with Bone Marrow Expansion and Muscle Fat Infiltration.

Reduced bone mass and density, hallmark features of osteopenia and osteoporosis, significantly increase the risk of fractures, falls, and loss of mobility, especially in post-menopausal women and the elderly. This quantitative 7T MRI study examines the features of fibular bone thinning and bone mineral density loss (BMD) in 107 individuals (43F/64M) across various ages, body mass indices (BMIs), and ethnicities. Women had significantly lower cross-sectional bone wall thickness (BT) and bone tissue area (BA), along with greater BMD loss compared to men in those over age 50 ( = 77), but not in the younger group ( = 30).

Sex Differences in Fat Distribution and Muscle Fat Infiltration in the Lower Extremity: A Retrospective Diverse-Ethnicity 7T MRI Study in a Research Institute Setting in the USA.

Fat infiltration in skeletal muscle is related to declining muscle strength, whereas excess subcutaneous fat is implicated in the development of metabolic diseases. Using multi-slice axial T2-weighted (T2w) MR images, this retrospective study characterized muscle fat infiltration (MFI) and fat distribution in the lower extremity of 107 subjects (64M/43F, age 11-79 years) with diverse ethnicities (including White, Black, Latino, and Asian subjects). MRI data analysis shows that MFI, evaluated by the relative intensities of the pixel histogram profile in the calf muscle, tends to increase with both age and BMI.

Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

Background: We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation.

Methods: Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO, and muscle oxygen diffusive conductance.

H and P magnetic resonance spectroscopy reveals potential pathogenic and biomarker metabolite alterations in Lafora disease.

Lafora disease is a fatal teenage-onset progressive myoclonus epilepsy and neurodegenerative disease associated with polyglucosan bodies. Polyglucosans are long-branched and as a result precipitation- and aggregation-prone glycogen. In mouse models, downregulation of glycogen synthase, the enzyme that elongates glycogen branches, prevents polyglucosan formation and rescues Lafora disease.

Association between dietary phosphate intake and skeletal muscle energetics in adults without cardiovascular disease.

Highly bioavailable inorganic phosphate (Pi) is present in large quantities in the typical Western diet and represents a large fraction of total phosphate intake. Dietary Pi excess induces exercise intolerance and skeletal muscle mitochondrial dysfunction in normal mice. However, the relevance of this to humans remains unknown.

17β-Estradiol Effects in Skeletal Muscle: A P MR Spectroscopic Imaging (MRSI) Study of Young Females during Early Follicular (EF) and Peri-Ovulation (PO) Phases.

The natural variation in estrogen secretion throughout the female menstrual cycle impacts various organs, including estrogen receptor (ER)-expressed skeletal muscle. Many women commonly experience increased fatigue or reduced energy levels in the days leading up to and during menstruation, when blood estrogen levels decline. Yet, it remains unclear whether endogenous 17β-estradiol, a major estrogen component, directly affects the energy metabolism in skeletal muscle due to the intricate and fluctuating nature of female hormones.

Evidence of brain target engagement in Parkinson's disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials.

Background: Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson's disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models.

Potassium Magnesium Citrate Is Superior to Potassium Chloride in Reversing Metabolic Side Effects of Chlorthalidone.

Background: Thiazide diuretics (TD) are the first-line treatment of hypertension because of its consistent benefit in lowering blood pressure and cardiovascular risk. TD is also known to cause an excess risk of diabetes, which may limit long-term use. Although potassium (K) depletion was thought to be the main mechanism of TD-induced hyperglycemia, TD also triggers magnesium (Mg) depletion.

ATP line splitting in association with reduced intracellular magnesium and pH: a brain P MR spectroscopic imaging (MRSI) study of pediatric patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGADs).

Over the past four decades, ATP, the obligatory energy molecule for keeping all cells alive and functioning, has been thought to contribute only one set of signals in brain P MR spectra. Here we report for the first time the observation of two separate β-ATP peaks in brain spectra acquired from patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGADs) using 3D MRSI at 7 T. In voxel spectra with β-ATP line splitting, these two peaks are separated by 0.

P-MRS of healthy human brain: Measurement of guanosine diphosphate mannose at 7 T.

Guanosine diphosphate mannose (GDP-Man) is the donor substrate required for mannosylation in the synthesis of glycoproteins, glycolipids and the newly discovered glycoRNA. Normal GDP-Man biosynthesis plays a crucial role in support of a variety of cellular functions, including cell recognition, cell communication and immune responses against viruses. Here, we report the detection of GDP-Man in human brain for the first time, using P MRS at 7 T.

Phosphate Brain Energy Metabolism and Cognition in Alzheimer's Disease: A Spectroscopy Study Using Whole-Brain Volume-Coil Phosphorus Magnetic Resonance Spectroscopy at 7Tesla.

Introduction: Mitochondrial dysfunction is a neurometabolic hallmark signaling abnormal brain energy metabolism (BEM) targeted as a potential early marker of Alzheimer's disease (AD). Advanced imaging technologies, such as phosphorus magnetic resonance spectroscopy (P MRS) at ultra-high-field (UHF) magnetic strength 7T, provide sensitive phosphate-BEM (p-BEM) data with precision. The study's first goal was to develop a methodology to measure phosphate energy and membrane metabolites simultaneously across the whole-brain using volume-coil P MRS at 7T in three groups-cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and AD.

P-MRS of the healthy human brain at 7 T detects multiple hexose derivatives of uridine diphosphate glucose.

Nucleotide sugars are required for the synthesis of glycoproteins and glycolipids, which play crucial roles in many cellular functions such as cell communication and immune responses. Uridine diphosphate-glucose (UDP-Glc) was previously believed to be the only nucleotide sugar detectable in brain by P-MRS. Using spectra of high SNR and high resolution acquired at 7 T, we showed that multiple nucleotide sugars are coexistent in brain and can be measured simultaneously.

Relationship of Parieto-Occipital Brain Energy Phosphate Metabolism and Cognition Using P MRS at 7-Tesla in Amnestic Mild Cognitive Impairment.

Background: The human brain has high energy requirements that continuously support healthy neuronal activity and cognition. A disruption in brain energy metabolism (BEM) may contribute to early neuropathological changes such as accumulation of β-amyloid and tau in vulnerable populations. One such population is amnestic mild cognitive impairment (aMCI) where some individuals are at risk for developing dementia, i.

Quantitative measurement of redox state in human brain by P MRS at 7T with spectral simplification and inclusion of multiple nucleotide sugar components in data analysis.

Purpose: To develop a simplified method for quantitative measurement of NAD /NADH (nicotinamide adenine dinucleotides) levels in human brain by P MRS without interference from the α-ATP signal and with inclusion of multiple UDP-sugar components.

Methods: Simple pulse-acquire P MR spectra were collected at 7T with and without a frequency-selective inversion pulse to remove the dominant α-ATP signal from the underlying NAD(H) signal. Careful inspection of the P signal at -9.

Modular P wideband inversion transfer for integrative analysis of adenosine triphosphate metabolism, T relaxation and molecular dynamics in skeletal muscle at 7T.

Purpose: For efficient and integrative analysis of de novo adenosine triphosphate (ATP) synthesis, creatine-kinase-mediated ATP synthesis, T relaxation time, and ATP molecular motion dynamics in human skeletal muscle at rest.

Methods: Four inversion-transfer modules differing in center inversion frequency were combined to generate amplified magnetization transfer (MT) effects in targeted MT pathways, including Pi ↔ γ-ATP, PCr ↔ γ-ATP, and P ↔ P . MT effects from both forward and reverse exchange kinetic pathways were acquired to reduce potential bias and confounding factors in integrated data analysis.

Unveiling a hidden P signal coresonating with extracellular inorganic phosphate by outer-volume-suppression and localized P MRS in the human brain at 7T.

Purpose: The study was undertaken to demonstrate that there is more than 1 component in the extracellular P P signal ( Piex) acquired from human head using nonlocalized P MRS.

Methods: Outer-volume-suppression (OVS) saturation and 1D/2D P CSI were utilized to reveal the presence of an additional component in the Piex signal.

Results: 67% of the head extracellular P signal was attenuated upon OVS saturation of the peripheral meningeal tissues, likely reflecting elimination of the P signal in the meningeal fluids (the blood and CSF).

Intramyocellular lipid excess in the mitochondrial disorder MELAS: MRS determination at 7T.

Objective: There is a paucity of objective, quantifiable indicators of mitochondrial disease available for clinical and scientific investigation.

Methods: To this end, we explore intramyocellular lipid (IMCL) accumulation noninvasively by 7T magnetic resonance spectroscopy (MRS) as a reporter of metabolic dysfunction in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). We reasoned that mitochondrial dysfunction may impair muscle fat metabolism, resulting in lipid deposition (as is sometimes observed in biopsies), and that MRS is well suited to quantify these lipids.

Efficient P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T.

Purpose: To develop an efficient P magnetic resonance spectroscopy (MRS) method for measuring creatine kinase (CK) activity, adenosine triphosphate (ATP) synthesis, and motion dynamics in the human brain at 7 Tesla (T).

Methods: Three band inversion modules differing in center frequency were used to induce magnetization transfer (MT) effect in three exchange pathways: (i) CK-mediated reaction PCr → γ-ATP; (ii) de novo ATP synthesis Pi → γ-ATP; and (iii) ATP intramolecular P- P cross-relaxation γ-(α-) ↔ β-ATP. The resultant MT data were analyzed using a 5-pool model in the format of magnetization matrix according to Bloch-McConnell-Solomon formalism.

Band inversion amplifies P- P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by P MRS at 7 T.

Purpose: To develop an improved method to measure the P nuclear Overhauser effect (NOE) for evaluation of adenosine triphosphate (ATP) dynamics in terms of correlation time (τ ), and contribution of dipole-dipole (DD) and chemical shift anisotropy (CSA) mechanisms to T relaxation of ATP in human brain.

Methods: The NOE of ATP in human brain was evaluated by monitoring changes in magnetization in the β-ATP signal following a band inversion of all downfield P resonances. The magnetization changes observed were analyzed using the Bloch-McConnell-Solomon formulation to evaluate the relaxation and motion dynamic parameters that describe interactions of ATP with cellular solids in human brain tissue.

(31)P-MRS of healthy human brain: ATP synthesis, metabolite concentrations, pH, and T1 relaxation times.

The conventional method for measuring brain ATP synthesis is (31)P saturation transfer (ST), a technique typically dependent on prolonged pre-saturation with γ-ATP. In this study, ATP synthesis rate in resting human brain is evaluated using EBIT (exchange kinetics by band inversion transfer), a technique based on slow recovery of γ-ATP magnetization in the absence of B1 field following co-inversion of PCr and ATP resonances with a short adiabatic pulse. The unidirectional rate constant for the Pi → γ-ATP reaction is 0.

A simple approach to evaluate the kinetic rate constant for ATP synthesis in resting human skeletal muscle at 7 T.

Inversion transfer (IT) is a well-established technique with multiple attractive features for analysis of kinetics. However, its application in measurement of ATP synthesis rate in vivo has lagged behind the more common saturation transfer (ST) techniques. One well-recognized issue with IT is the complexity of data analysis in comparison with much simpler analysis by ST.

Amplification of the effects of magnetization exchange by (31) P band inversion for measuring adenosine triphosphate synthesis rates in human skeletal muscle.

Purpose: The goal of this study was to amplify the effects of magnetization exchange between γ-adenosine triphosphate (ATP) and inorganic phosphate (Pi) for evaluation of ATP synthesis rates in human skeletal muscle.

Methods: The strategy works by simultaneously inverting the (31) P resonances of phosphocreatine (PCr) and ATP using a wide bandwidth, adiabatic inversion radiofrequency pulse followed by observing dynamic changes in intensity of the noninverted Pi signal versus the delay time between the inversion and observation pulses. This band inversion technique significantly delays recovery of γ-ATP magnetization; consequently, the exchange reaction, Pi ↔ γ-ATP, is readily detected and easily analyzed.