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•Permanent MCAO mice exhibited increased GuanCEST in stroke lesions with low B1 CEST, along with a significant decrease in Guan and amide CEST with high B1, due to pH changes.•AmineCEST is a highly sensitive MRI contrast for detecting reperfusion damage at high MRI fields, as demonstrated in transient MCAO mice.•At lower B1 values, the changes in GuanCEST within stroke lesions were primarily driven by increased creatine concentrations in permanent MCAO mice, which remained stable in transient MCAO mice.•While Guan and amineCEST are highly sensitive in delineating stroke lesions, amideCEST is better suited for precise pH mapping. This study aims to investigate the variations in guanidino (Guan), amine and amide chemical exchange saturation transfer (CEST) contrasts in ischemic stroke using permanent middle cerebral artery occlusion (pMCAO) and transient MCAO (tMCAO) models at high (9.4T) and clinical (3T) MRI fields. CEST contrasts were extracted using the Polynomial and Lorentzian Line-shape Fitting (PLOF) method. Both pMCAO and tMCAO models were utilized to examine the B1-dependence patterns and pH sensitivity of the different CEST contrasts in ischemic lesions compared to contralateral region. At 9.4T, GuanCEST showed the highest signal in the contralateral hemisphere for both stroke models, followed by lower signals from amideCEST and amineCEST, with maximum signals at B1=1.2 μT for all CEST contrasts. In both stroke models, GuanCEST exhibited a significant decrease of 1.15–1.5 % in stroke lesions compared to the contralateral hemisphere (ΔGuanCEST) at an optimal B1 range of 1.2–1.6 μT at 9.4T. This represents more than double the pH sensitivity compared to amideCEST, which showed a reduction of 0.5–0.62 % under the same B1 conditions. In the tMCAO model, amineCEST increased by 3.85 % in the stroke lesion compared to the contralateral hemisphere at an optima B1 range of 1.6–2.5 μT. In contrast, for the pMCAO model, amineCEST increased by 0.87–1.0 % in the stroke lesion. At lower B1 values (<0.8 μT at 9.4T and <0.4 μT at 3T), the GuanCEST changes in the stroke lesion were dominated by creatine concentration changes, which increased in the pMCAO and remained stable in the tMCAO. While GuanCEST and amineCEST are highly sensitive for delineating stroke lesions, amideCEST is more suitable for precise pH mapping as it is not influenced by metabolite changes within the stroke lesion. Additionally, at low B1 values, amideCEST and GuanCEST can be used to map protein and creatine concentrations separately, since they are independent of pH changes at these lower B1 values. Lastly, amineCEST serves as a highly sensitive MRI contrast for detecting reperfusion damage at high MRI fields.

•Echo-less 3D-MRSI at 7T provides high-resolution metabolic maps in just 8 min.•Voxel-wise analysis reveals distinct metabolic patterns in multiple sclerosis.•Elevated myo-inositol primarily affects periventricular white matter beyond lesions.•NAA reductions exceed mI elevation, notably in prefrontal, motor, and sensory areas.•NAA reductions strongly correlate with MS disability score in motor/cognitive areas. To assess topographical patterns of metabolic abnormalities in the cerebrum of multiple sclerosis (MS) patients and their relationship to clinical disability using rapid echo-less 3D-MR spectroscopic imaging (MRSI) at 7T. This study included 26 MS patients (13 women; median age 34) and 13 age- and sex-matched healthy controls (7 women; median age 33). Metabolic maps were obtained using echo-less 3D-MRSI at 7T with a 64 × 64 × 33 matrix and a nominal voxel size of 3.4 × 3.4 × 4 mm³ in an 8-minute scan. After spatial normalization, voxel-wise comparisons between MS and controls were conducted to identify clusters of metabolic abnormalities, while correlations with clinical disability were analyzed using Expanded Disability Status Scale (EDSS) scores. Statistical mapping (FWE-corrected; P<.05) revealed elevated myo-inositol to total creatine (mI/tCr) ratios in the bilateral periventricular white matter and reduced N-acetylaspartate to total creatine (NAA/tCr) within and beyond lesions, notably near the lateral ventricles, cingulate gyrus, and superior frontal gyrus. Patients with sustained disability (EDSS≥2) showed additional reductions in the posterior parietal lobe. A strong negative association was found between NAA/tCr and EDSS in the precentral gyrus (Spearman's rank ρ=-0.58, P=.005), and a moderate positive association between mI/NAA and EDSS in the precentral and superior frontal gyri (ρ=0.47, P=.015). This study highlights the ability of 3D-MRSI at 7T to map widespread metabolic abnormalities in MS, with NAA reductions in prefrontal, motor, and sensory areas, linked to neuroaxonal damage and disability progression, and elevated mI in periventricular regions, reflecting gliosis.

Psychotic Disorders such as schizophrenia (SZ) and bipolar disorder (BD) are characterized by abnormal functional connectivity (FC) within neural networks such as the default mode network (DMN), as well as attenuated anticorrelation between DMN and task-positive networks (TPN). Bioenergetic processes are critical for synaptic connectivity and are also abnormal in psychotic disorders. We therefore examined the association between brain energy metabolism and FC in psychotic disorders. 31P magnetization transfer spectroscopy from medial prefrontal cortex (MPFC) and whole-brain fMRI data were collected from demographically matched groups of SZ, BD, and healthy control (HC) subjects. The creatine kinase (CK) reaction flux calculated from spectroscopy was used as an index of regional energy production rate. FC maps were generated with MPFC as the seed region. Compared to HC, SZ showed significantly lower CK flux, while both BD and SZ patients showed decreased anticorrelation between MPFC and TPN. CK flux was significantly correlated with FC between MPFC and other DMN nodes in HC. This positive correlation was reduced modestly in BD and strongly in SZ. CK flux was negatively correlated with the anticorrelation between MPFC and TPN in HC, but this relationship was not observed in BD or SZ. These results indicate that MPFC energy metabolism rates are associated with stronger FC within networks and stronger anticorrelation between networks in HC. However, this association is decreased in SZ and BD, where bioenergetic and FC abnormalities are evident. This pattern may suggest that impairment in energy production in psychotic disorders underlies the impaired neural connectivity.

Despite the essential role of the brain energy generated from ATP hydrolysis in supporting cortical neuronal activity and brain function, it is challenging to noninvasively image and directly quantify the energy expenditure in the human brain. In this study, we applied an advanced in vivo31P MRS imaging approach to obtain regional cerebral metabolic rates of high-energy phosphate reactions catalyzed by ATPase (CMRATPase) and creatine kinase (CMRCK), and to determine CMRATPase and CMRCK in pure gray mater (GM) and white mater (WM), respectively. It was found that both ATPase and CK rates are three times higher in GM than WM; and CMRCK is seven times higher than CMRATPase in GM and WM. Among the total brain ATP consumption in the human cortical GM and WM, 77% of them are used by GM in which approximately 96% is by neurons. A single cortical neuron utilizes approximately 4.7billion ATPs per second in a resting human brain. This study demonstrates the unique utility of in vivo31P MRS imaging modality for direct imaging of brain energy generated from ATP hydrolysis, and provides new insights into the human brain energetics and its role in supporting neuronal activity and brain function. ► The ATP utilization rate is three times higher in GM than WM in the human brain. ► The majority of the cerebral ATP energy is utilized by cortical neurons in humans. ► 4.7 billion ATP molecules are utilized by a cortical neuron each second in humans. ► A resting-state human brain utilizes ~5.7 kg ATP/day, 5 times of the brain weight.

Previous studies have linked cardiac dysfunction to loss of metabolites in the creatine kinase system. Chemical exchange saturation transfer (CEST) is a promising metabolic cardiovascular magnetic resonance (CMR) imaging technique and has been applied in the heart for creatine mapping. However, current limitations include: (a) long scan time, (b) residual cardiac and respiratory motion, and (c) B0 field variations induced by respiratory motion. An improved CEST CMR technique was developed to address these problems. Animals with chronic myocardial infarction (N = 15) were scanned using the proposed CEST CMR technique and a late gadolinium enhancement (LGE)  sequence as reference. The major improvements of the CEST CMR technique are: (a) Images were acquired by single-shot FLASH, significantly increasing the scan efficiency. (b) All images were registered to reduce the residual motion. (c) The acquired Z-spectrum was analyzed using 3-pool-model Lorentzian-line fitting to generate CEST signal, reducing the impact of B0 field shifting due to respiratory motion. Feasibility of the technique was tested in a porcine model with chronic myocardial infarction. CEST signal was measured in the scar, border zone and remote myocardium. Initial studies were performed in one patient. In all animals, healthy remote myocardial CEST signal was elevated (0.16 ± 0.02) compared to infarct CEST signal (0.09 ± 0.02, P < 0.001) and the border zone (0.12 ± 0.02, P < 0.001). For both animal and patient studies, the hypointense regions in the CEST contrast maps closely match the bright areas in the LGE images. The proposed CEST CMR technique was developed to address long scan times, respiratory and cardiac motion, and B0 field variations. Lower CEST signal in bright region of the LGE image is consistent with the fact that myocardial infarction has reduced metabolic activity.

Age and sex differences in brain metabolite concentrations in early life are not well understood. We examined the associations of age and sex with brain metabolite levels in healthy neonates, and investigated the associations between neonatal brain metabolite concentrations and developmental outcomes. Forty-one infants (36–42 gestational weeks at birth; 39% female) of predominantly Hispanic/Latina mothers (mean 18 years of age) underwent MRI scanning approximately two weeks after birth. Multiplanar chemical shift imaging was used to obtain voxel-wise maps of N-acetylaspartate (NAA), creatine, and choline concentrations across the brain. The Bayley Scales of Infant and Toddler Development, a measure of cognitive, language, and motor skills, and mobile conjugate reinforcement paradigm, a measure of learning and memory, were administered at 4 months of age. Findings indicated that postmenstrual age correlated positively with NAA concentrations in multiple subcortical and white matter regions. Creatine and choline concentrations showed similar but less pronounced age related increases. Females compared with males had higher metabolite levels in white matter and subcortical gray matter. Neonatal NAA concentrations were positively associated with learning and negatively associated with memory at 4 months. Age-related increases in NAA, creatine, and choline suggest rapid development of neuronal viability, cellular energy metabolism, and cell membrane turnover, respectively, during early life. Females may undergo earlier and more rapid regional developmental increases in the density of viable neurons compared to males.

Mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2 ) in the majority of people with grade 2 and 3 gliomas is associated with elevated levels of 2-hydroxyglutarate (2HG) within the tumor. As harboring IDH1 or IDH2 mutations confers a considerable survival benefit in these individuals, there has been considerable interest in studying this metabolite as a potential biomarker. Here, Changho Choi et al . report the successful noninvasive detection of 2HG in 30 subjects with gliomas using a proton magnetic resonance spectroscopy approach. Mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2 ) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D -2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impaired social interaction, and restricted and repetitive patterns of behavior. ASD presents as a clinical spectrum, with variable levels of severity and multiple co-occurring conditions. The etiology of ASD may involve hundreds of genes and there is evidence that neurotransmitter and synaptic (NS) pathways are implicated. Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) has made it possible to study the concentration of brain neurometabolites and compare their levels in the brains of ASD and control individuals. We integrated genetic variants in NS genes with 1 H-MRS analysis, and identified 12 predicted damaging variants (PDVs) in 12 NS genes in 10 ASD individuals, most mapping to genes involved in Gamma-aminobutyric acid (GABA) and glutamate pathways. Total creatine (tCr) and total N-acetyl aspartate (tNAA), markers of bioenergetics and neuronal metabolism, respectively, were lower in ASD patients with genetic alterations in NS genes compared to a control group without ASD. We conclude that PDVs in NS genes that are important for the regulation of glutamate or involved in GABAergic functions are associated with neurometabolic alterations, and that dysfunction in glutamatergic and/or GABAergic pathways may be implicated as these pathways are linked to the metabolic measures altered in cases.

Background Little is known about the disease distribution and severity detected by T1-mapping in Duchenne muscular dystrophy (DMD). Furthermore, the correlation between skeletal muscle T1-values and clinical assessments is less studied. Hence, the purposes of our study are to investigate quantitative T1-mapping in detecting the degree of disease involvement by detailed analyzing the hip and thigh muscle, future exploring the predicting value of T1-mapping for the clinical status of DMD. Methods Ninety-two DMD patients were included. Grading fat infiltration and measuring the T1-values of 19 pelvic and thigh muscles (right side) in axial T1-weighted images (T1WI) and T1-maps, respectively, the disease distribution and severity were evaluated and compared. Clinical assessments included age, height, weight, BMI, wheelchair use, timed functional tests, NorthStar ambulatory assessment (NSAA) score, serum creatine kinase (CK) level. Correlation analysis were performed between the muscle T1-value and clinical assessments. Multiple linear regression analysis was conducted for the independent association of T1-value and motor function. Results The gluteus maximus had the lowest T1-value, and the gracilis had the highest T1-value. T1-value decreased as the grade of fat infiltration increased scored by T1WI ( P  < 0.001). The decreasing of T1-values was correlated with the increase of age, height, weight, wheelchair use, and timed functional tests ( P  < 0.05). T1-value correlated with NSAA (r = 0.232-0.721, P  < 0.05) and CK (r = 0.208-0.491, P  < 0.05) positively. T1-value of gluteus maximus, tensor fascia, vastus lateralis, vastus intermedius, vastus medialis, and adductor magnus was independently associated with the clinical motor function tests ( P  < 0.05). Interclass correlation coefficient (ICC) analysis and Bland-Altman plots showed excellent inter-rater reliability of T1-value region of interest (ROI) measurements. Conclusion T1-mapping can be used as a quantitative biomarker for disease involvement, further assessing the disease severity and predicting motor function in DMD.

Insomnia is closely related to major depressive disorder (MDD) both cross-sectionally and longitudinally, and as such, offers potential opportunities to refine our understanding of the neurobiology of both sleep and mood disorders. Clinical and basic science data suggest a role for reduced γ-aminobutyric acid (GABA) in both MDD and primary insomnia (PI). Here, we have utilized single-voxel proton magnetic spectroscopy (1H-MRS) at 4 Tesla to examine GABA relative to total creatine (GABA/Cr) in the occipital cortex (OC), anterior cingulate cortex (ACC), and thalamus in 20 non-medicated adults with PI (12 women) and 20 age- and sex-matched healthy sleeper comparison subjects. PI subjects had significantly lower GABA/Cr in the OC (p=0.0005) and ACC (p=0.03) compared with healthy sleepers. There was no significant difference in thalamic GABA/Cr between groups. After correction for multiple comparisons, GABA/Cr did not correlate significantly with insomnia severity measures among PI subjects. This study is the first to demonstrate regional reductions of GABA in PI in the OC and ACC. Reductions in GABA in similar brain regions in MDD using 1H-MRS suggest a common reduction in cortical GABA among PI and mood disorders.