RESUMEN

BACKGROUND: Cystathionine accumulates selectively in 1p/19q-codeleted gliomas, and can serve as a possible noninvasive biomarker. This study aims to optimize the echo time (TE) of point-resolved spectroscopy (PRESS) for cystathionine detection in gliomas, and evaluate the diagnostic accuracy of PRESS for 1p/19q-codeletion identification. METHODS: The TE of PRESS was optimized with numerical and phantom analysis to better resolve cystathionine from the overlapping aspartate multiplets. The optimized and 97 ms TE PRESS were then applied to 84 prospectively enrolled patients suspected of glioma or glioma recurrence to examine the influence of aspartate on cystathionine quantification by fitting the spectra with and without aspartate. The diagnostic performance of PRESS for 1p/19q-codeleted gliomas were assessed. RESULTS: The TE of PRESS was optimized as (TE1, TE2) = (17 ms, 28 ms). The spectral pattern of cystathionine and aspartate were consistent between calculation and phantom. The mean concentrations of cystathionine in vivo fitting without aspartate were significantly higher than those fitting with full basis-set for 97 ms TE PRESS (1.97 ± 2.01 mM vs. 1.55 ± 1.95 mM, p < 0.01), but not significantly different for 45 ms method (0.801 ± 1.217 mM and 0.796 ± 1.217 mM, p = 0.494). The cystathionine concentrations of 45 ms approach was better correlated with those of edited MRS than 97 ms counterparts (r = 0.68 vs. 0.49, both p < 0.01). The sensitivity and specificity for discriminating 1p/19q-codeleted gliomas were 66.7% and 73.7% for 45 ms method, and 44.4% and 52.5% for 97 ms method, respectively. CONCLUSION: The 45 ms TE PRESS yields more precise cystathionine estimates than the 97 ms method, and is anticipated to facilitate noninvasive diagnosis of 1p/19q-codeleted gliomas, and treatment response monitoring in those patients. Medium diagnostic performance of PRESS for 1p/19q-codeleted gliomas were observed, and warrants further investigations.

Asunto(s)

Neoplasias Encefálicas , Cistationina , Glioma , Humanos , Glioma/diagnóstico por imagen , Masculino , Cistationina/análisis , Femenino , Neoplasias Encefálicas/diagnóstico por imagen , Persona de Mediana Edad , Adulto , Estudios Prospectivos , Fantasmas de Imagen , Anciano , Espectroscopía de Resonancia Magnética/métodos , Adulto Joven , Biomarcadores de Tumor/análisis , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análisis

RESUMEN

AIMS: Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON). METHODS: Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5 T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions. RESULTS: Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON. CONCLUSIONS: Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability.

Asunto(s)

Alcoholismo , Aterosclerosis , Encéfalo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Alcoholismo/metabolismo , Alcoholismo/patología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Adulto , Aterosclerosis/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Colina/metabolismo , Hipertensión/metabolismo , Hiperlipidemias/metabolismo , Inositol/metabolismo , Espectroscopía de Resonancia Magnética , Creatina/metabolismo

RESUMEN

The effectiveness of ß-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic ß-lactamase enzymes. Depending on the class of ß-lactamase present, ß-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-ß-lactamases (MBLs) require active site Zn2+ ions, whereas serine-ß-lactamases (SBLs) deploy a catalytic serine residue. The result in both cases is drug inactivation via the opening of the ß-lactam warhead of the antibiotic. MBLs confer resistance to most ß-lactams and are non-susceptible to SBL inhibitors, including recently approved diazabicyclooctanes, such as avibactam; consequently, these enzymes represent a growing threat to public health. Aspergillomarasmine A (AMA), a fungal natural product, can rescue the activity of the ß-lactam antibiotic meropenem against MBL-expressing bacterial strains. However, the effectiveness of this ß-lactam/ß-lactamase inhibitor combination against bacteria producing multiple ß-lactamases remains unknown. We systematically investigated the efficacy of AMA/meropenem combination therapy with and without avibactam against 10 Escherichia coli and 10 Klebsiella pneumoniae laboratory strains tandemly expressing single MBL and SBL enzymes. Cell-based assays demonstrated that laboratory strains producing NDM-1 and KPC-2 carbapenemases were resistant to the AMA/meropenem combination but became drug-susceptible upon adding avibactam. We also probed these combinations against 30 clinical isolates expressing multiple ß-lactamases. E. coli, Enterobacter cloacae, and K. pneumoniae clinical isolates were more susceptible to AMA, avibactam, and meropenem than Pseudomonas aeruginosa and Acinetobacter baumannii isolates. Overall, the results demonstrate that a triple combination of AMA/avibactam/meropenem has potential for empirical treatment of infections caused by multiple ß-lactamase-producing bacteria, especially Enterobacterales.

Asunto(s)

Antibacterianos , Compuestos de Azabiciclo , Escherichia coli , Meropenem , Pruebas de Sensibilidad Microbiana , beta-Lactamasas , Compuestos de Azabiciclo/farmacología , beta-Lactamasas/metabolismo , beta-Lactamasas/genética , Antibacterianos/farmacología , Meropenem/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Inhibidores de beta-Lactamasas/farmacología , Humanos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/genética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Combinación de Medicamentos , Enterobacter cloacae/efectos de los fármacos , Enterobacter cloacae/enzimología , Ácido Aspártico/análogos & derivados

RESUMEN

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Asunto(s)

Colina , Lipopolisacáridos , Espectroscopía de Resonancia Magnética , Microglía , Lipopolisacáridos/farmacología , Microglía/metabolismo , Animales , Colina/metabolismo , Masculino , Espectroscopía de Resonancia Magnética/métodos , Enfermedades Neuroinflamatorias/metabolismo , Creatina/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Encéfalo/metabolismo , Imagen de Difusión por Resonancia Magnética/métodos , Tálamo/metabolismo , Femenino

RESUMEN

Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.

Asunto(s)

Encéfalo , Proteína C-Reactiva , Interleucina-6 , Humanos , Femenino , Embarazo , Encéfalo/metabolismo , Recién Nacido , Interleucina-6/metabolismo , Adolescente , Estudios Longitudinales , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Adulto Joven , Estudios Prospectivos , Adulto , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Creatina/metabolismo , Masculino , Lactante , Colina/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Imagen de Difusión Tensora , Espectroscopía de Resonancia Magnética , Desarrollo Infantil/fisiología

RESUMEN

Converging data show that exposure to maternal immune activation (MIA) in utero alters brain development in animals and increases the risk of neurodevelopmental disorders in humans. A recently developed non-human primate MIA model affords opportunities for studies with uniquely strong translational relevance to human neurodevelopment. The current longitudinal study used 1H-MRS to investigate the developmental trajectory of prefrontal cortex metabolites in male rhesus monkey offspring of dams (n = 14) exposed to a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid (Poly IC), in the late first trimester. Brain metabolites in these animals were compared to offspring of dams that received saline (n = 10) or no injection (n = 4). N-acetylaspartate (NAA), glutamate, creatine, choline, myo-inositol, taurine, and glutathione were estimated from PRESS and MEGA-PRESS acquisitions obtained at 6, 12, 24, 36, and 45 months of age. Prior investigations of this cohort reported reduced frontal cortical gray and white matter and subtle cognitive impairments in MIA offspring. We hypothesized that the MIA-induced neurodevelopmental changes would extend to abnormal brain metabolite levels, which would be associated with the observed cognitive impairments. Prefrontal NAA was significantly higher in the MIA offspring across all ages (p < 0.001) and was associated with better performance on the two cognitive measures most sensitive to impairment in the MIA animals (both p < 0.05). Myo-inositol was significantly lower across all ages in MIA offspring but was not associated with cognitive performance. Taurine was elevated in MIA offspring at 36 and 45 months. Glutathione did not differ between groups. MIA exposure in male non-human primates is associated with altered prefrontal cortex metabolites during childhood and adolescence. A positive association between elevated NAA and cognitive performance suggests the hypothesis that elevated NAA throughout these developmental stages reflects a protective or resilience-related process in MIA-exposed offspring. The potential relevance of these findings to human neurodevelopmental disorders is discussed.

Asunto(s)

Encéfalo , Macaca mulatta , Poli I-C , Corteza Prefrontal , Efectos Tardíos de la Exposición Prenatal , Animales , Masculino , Femenino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Embarazo , Encéfalo/metabolismo , Poli I-C/farmacología , Corteza Prefrontal/metabolismo , Inositol/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Creatina/metabolismo , Taurina/metabolismo , Colina/metabolismo , Modelos Animales de Enfermedad , Ácido Glutámico/metabolismo , Glutatión/metabolismo , Estudios Longitudinales

RESUMEN

OBJECTIVES: The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses. METHODS: We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus. RESULTS: The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A1c (HbA1c) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre. CONCLUSIONS: Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN. SIGNIFICANCE: Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes.

Asunto(s)

Encéfalo , Diabetes Mellitus Tipo 1 , Neuropatías Diabéticas , Espectroscopía de Resonancia Magnética , Fenotipo , Humanos , Femenino , Masculino , Diabetes Mellitus Tipo 1/metabolismo , Adulto , Persona de Mediana Edad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/diagnóstico por imagen , Espectroscopía de Resonancia Magnética/métodos , Ácido Aspártico/análogos & derivados

RESUMEN

PURPOSE: The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS: We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS: There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS: Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

Asunto(s)

Enfermedad de Alzheimer , Apolipoproteína E4 , Biomarcadores , Espectroscopía de Resonancia Magnética , Proteínas tau , Humanos , Apolipoproteína E4/genética , Anciano , Femenino , Masculino , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Proteínas tau/metabolismo , Estudios Retrospectivos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano de 80 o más Años , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Alelos , Persona de Mediana Edad , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/metabolismo

RESUMEN

The posterior cingulate cortex (PCC) is a key hub of the default mode network and is known to play an important role in attention. Using ultra-high field 7 Tesla magnetic resonance spectroscopy (MRS) to quantify neurometabolite concentrations, this exploratory study investigated the effect of the concentrations of myo-inositol (Myo-Ins), glutamate (Glu), glutamine (Gln), aspartate or aspartic acid (Asp) and gamma-amino-butyric acid (GABA) in the PCC on attention in forty-six healthy participants. Each participant underwent an MRS scan and cognitive testing, consisting of a trail-making test (TMT A/B) and a test of attentional performance. After a multiple regression analysis and bootstrapping for correction, the findings show that Myo-Ins and Asp significantly influence (p < 0.05) attentional tasks. On one hand, Myo-Ins shows it can improve the completion times of both TMT A and TMT B. On the other hand, an increase in aspartate leads to more mistakes in Go/No-go tasks and shows a trend towards enhancing reaction time in Go/No-go tasks and stability of alertness without signal. No significant (p > 0.05) influence of Glu, Gln and GABA was observed.

Asunto(s)

Atención , Giro del Cíngulo , Espectroscopía de Resonancia Magnética , Humanos , Atención/fisiología , Masculino , Femenino , Adulto , Espectroscopía de Resonancia Magnética/métodos , Giro del Cíngulo/metabolismo , Adulto Joven , Ácido Glutámico/metabolismo , Inositol/metabolismo , Glutamina/metabolismo , Ácido Aspártico/metabolismo , Ácido Aspártico/análogos & derivados , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/análisis

RESUMEN

Proton magnetic resonance spectroscopy (1H-MRS) has shown inconsistent alterations in the brain metabolites of individuals with chronic pain. We used 3T 1H-MRS to investigate the brain metabolites in the anterior cingulate cortex and thalamus of 22 patients with chronic mild pain and no gait disturbance and 22 healthy controls. The chronic-pain group included patients with chronic low back pain and/or osteoarthritis but none suffering from hypersensitivity. There were no significant between group-differences in glutamate, glutamate plus glutamine (Glx), N-acetylaspartate, glycerophosphorylcholine (GPC), glutamine, creatine plus phosphocreatine, or myo-inositol in the anterior cingulate cortex, but the patients showed a significant decrease in GPC, but not other metabolites, in the thalamus compared to the controls. The GPC values in the patients' thalamus were significantly correlated with pain components on the Short-Form McGill Pain Questionnaire (SF-MPQ-2) and affective empathy components on the Questionnaire of Cognitive and Affective Empathy (QCAE). The GPC in the patients' anterior cingulate cortex showed significant correlations with cognitive empathy components on the QCAE. Myo-inositol in the controls' anterior cingulate cortex and Glx in the patients' thalamus each showed significant relationships with peripheral responsivity on the QCAE. These significances were not significant after Bonferroni corrections. These preliminary findings indicate important roles of GPC, myo-inositol, and Glx in the brain of patients with chronic mild pain.

Asunto(s)

Dolor Crónico , Empatía , Giro del Cíngulo , Tálamo , Humanos , Giro del Cíngulo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Femenino , Masculino , Dolor Crónico/metabolismo , Dolor Crónico/diagnóstico por imagen , Persona de Mediana Edad , Tálamo/metabolismo , Tálamo/diagnóstico por imagen , Empatía/fisiología , Adulto , Inositol/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Anciano , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Dimensión del Dolor

RESUMEN

N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) are brain metabolites involved in some key neuronal functions within the brain, such as cognitive function. The aim of this study was to investigate whether Parkinson's disease (PD) with different cognitive status induces regional brain metabolite differences. 38 diagnosed PD patients, including 18 PD patients with normal cognitive (PDN), 20 PD subjects with cognitive impairment (PDMCI) and 25 healthy controls (HC) participated in this study. All subjects underwent a single-voxel proton MR spectroscopy (1H-MRS) on a 3T scanner. 1H-MRS were obtained from bilateral PCC, left thalamus and PFC regions in all subjects, respectively. Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. PDMCI patients showed a significant reduction of NAA, Cho and tCr in the PCC and left thalamus, compared to healthy controls; whereas lower levels of NAA and Cho in thalamus were found in PDN patients. Moreover, Cho and tCr levels were positively correlated with MMSE scores. Both NAA and tCr in PCC levels were positively correlated with MMSE and MoCA scores. The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. This study provides preliminary evidence that thalamic, PCC and PFC neurometabolic alterations occur in PD patients with cognition decline. Findings of this study indicate that NAA and tCr abnormalities in PCC and thalamus might be used as a biomarker to track cognitive decline in Parkinson's disease in clinical settings.

Asunto(s)

Ácido Aspártico , Colina , Disfunción Cognitiva , Creatina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Masculino , Femenino , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Creatina/metabolismo , Colina/metabolismo , Persona de Mediana Edad , Anciano , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Tálamo/metabolismo , Tálamo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Pruebas Neuropsicológicas

RESUMEN

Proton magnetic resonance spectroscopy (1H-MRS) allows measuring specific brain metabolic alterations in Huntington's disease (HD), and these metabolite profiles may serve as non-invasive biomarkers associated with disease progression. Despite this potential, previous findings are inconsistent. Accordingly, we performed a meta-analysis on available in vivo1H-MRS studies in premanifest (Pre-HD) and symptomatic HD stages (Symp-HD), and quantified neurometabolic changes relative to controls in 9 Pre-HD studies (227 controls and 188 mutation carriers) and 14 Symp-HD studies (326 controls and 306 patients). Our results indicated decreased N-acetylaspartate and creatine in the basal ganglia in both Pre-HD and Symp-HD. The overall level of myo-inositol was decreased in Pre-HD while increased in Symp-HD. Besides, Symp-HD patients showed more severe metabolism disruption than Pre-HD patients. Taken together, 1H-MRS is important for elucidating progressive metabolite changes from Pre-HD to clinical conversion; N-acetylaspartate and creatine in the basal ganglia are already sensitive at the preclinical stage and are promising biomarkers for tracking disease progression; overall myo-inositol is a possible characteristic metabolite for distinguishing HD stages.

Asunto(s)

Progresión de la Enfermedad , Enfermedad de Huntington , Espectroscopía de Protones por Resonancia Magnética , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/genética , Humanos , Espectroscopía de Protones por Resonancia Magnética/métodos , Creatina/metabolismo , Inositol/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen

RESUMEN

BACKGROUND AND OBJECTIVES: Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS: In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS: Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION: Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Asunto(s)

Ácido Aspártico , Corteza Cerebral , Ácido Glutámico , Inositol , Ácido gamma-Aminobutírico , Humanos , Persona de Mediana Edad , Femenino , Masculino , Adulto , Inositol/metabolismo , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Ácido Glutámico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Estudios Transversales , Corteza Cerebral/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Anciano , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Esclerosis Múltiple Crónica Progresiva/metabolismo , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto Joven , Espectroscopía de Protones por Resonancia Magnética

RESUMEN

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of 35 patients with schizophrenia spectrum disorders and 33 healthy controls who were also assessed with proton magnetic resonance spectroscopy at the anterior cingulate cortex using 3 Tesla scanner. Consistent with the hypothesis, greater lifetime stressor exposure was significantly associated with lower levels of N-acetylasparate (ß = -0.36, p = .005) and higher levels of lactate (ß = 0.43, p = .001). Moreover, these results were driven by patients, as these associations were significant for the patient but not control group. Though preliminary, these findings suggest a possible role for stress processes in the pathophysiology of abnormal neuroenergetics in schizophrenia.

Asunto(s)

Ácido Aspártico , Ácido Láctico , Esquizofrenia , Estrés Psicológico , Humanos , Masculino , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Esquizofrenia/diagnóstico por imagen , Femenino , Adulto , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Ácido Láctico/metabolismo , Ácido Láctico/sangre , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Persona de Mediana Edad , Adulto Joven , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/fisiopatología , Trastornos Psicóticos/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Espectroscopía de Resonancia Magnética

RESUMEN

PURPOSE: Demonstrate the feasibility and evaluate the performance of single-shot diffusion trace-weighted radial echo planar spectroscopic imaging (Trace DW-REPSI) for quantifying the trace ADC in phantom and in vivo using a 3T clinical scanner. THEORY AND METHODS: Trace DW-REPSI datasets were acquired in 10 phantom and 10 healthy volunteers, with a maximum b-value of 1601 s/mm2 and diffusion time of 10.75 ms. The self-navigation properties of radial acquisitions were used for corrections of shot-to-shot phase and frequency shift fluctuations of the raw data. In vivo trace ADCs of total NAA (tNAA), total creatine (tCr), and total choline (tCho) extrapolated to pure gray and white matter fractions were compared, as well as trace ADCs estimated in voxels within white or gray matter-dominant regions. RESULTS: Trace ADCs in phantom show excellent agreement with reported values, and in vivo ADCs agree well with the expected differences between gray and white matter. For tNAA, tCr, and tCho, the trace ADCs extrapolated to pure gray and white matter ranged from 0.18-0.27 and 0.26-0.38 µm2/ms, respectively. In sets of gray and white matter-dominant voxels, the values ranged from 0.21 to 0.27 and 0.24 to 0.31 µm2/ms, respectively. The overestimated trace ADCs from this sequence can be attributed to the short diffusion time. CONCLUSION: This study presents the first demonstration of the single-shot diffusion trace-weighted spectroscopic imaging sequence using radial echo planar trajectories. The Trace DW-REPSI sequence could provide an estimate of the trace ADC in a much shorter scan time compared to conventional approaches that require three separate measurements.

Asunto(s)

Encéfalo , Imagen de Difusión por Resonancia Magnética , Imagen Eco-Planar , Fantasmas de Imagen , Humanos , Imagen Eco-Planar/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Masculino , Femenino , Colina/metabolismo , Sustancia Blanca/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Voluntarios Sanos , Creatina/metabolismo , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Algoritmos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Espectroscopía de Resonancia Magnética/métodos

RESUMEN

BACKGROUND: It is widely known that sex differences have a significant impact on patients with major depressive disorder (MDD). This study aims to evaluate the sex-related connection between serum trace elements and changes in neurometabolism in the anterior cingulate cortex (ACC) of MDD patients. METHODS: 109 untreated MDD patients and 59 healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS) under resting conditions. We measured metabolic ratios in the ACC from both sides. Additionally, venous blood samples were taken from all participants to detect calcium (Ca), phosphorus, magnesium (Mg), copper (Cu), ceruloplasmin (CER), zinc (Zn), and iron (Fe) levels. We performed association and interaction analyses to explore the connections between the disease and gender. RESULTS: In individuals with MDD, the Cu/Zn ratio increased, while the levels of Mg, CER, Zn and Fe decreased. Male MDD patients had lower Cu levels, while female patients had an increased Cu/Zn ratio. We observed significant gender differences in Cu, CER and the Cu/Zn ratio in MDD. Male patients showed a reduced N-acetyl aspartate (NAA)/phosphocreatine + creatine (PCr + Cr) ratio in the left ACC. The NAA/PCr + Cr ratio decreased in the right ACC in patients with MDD. In the left ACC of male MDD patients, the Cu/Zn ratio was inversely related to the NAA/PCr + Cr ratio, and Fe levels were negatively associated with the GPC + PC/PCr + Cr ratio. CONCLUSIONS: Our findings highlight gender-specific changes in Cu homeostasis among male MDD patients. The Cu/Zn ratio and Fe levels in male MDD patients were significantly linked to neurometabolic alterations in the ACC.

Asunto(s)

Ácido Aspártico , Trastorno Depresivo Mayor , Giro del Cíngulo , Hierro , Oligoelementos , Zinc , Humanos , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/metabolismo , Masculino , Femenino , Giro del Cíngulo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Adulto , Oligoelementos/sangre , Oligoelementos/metabolismo , Zinc/sangre , Zinc/metabolismo , Hierro/metabolismo , Hierro/sangre , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Ácido Aspártico/sangre , Persona de Mediana Edad , Factores Sexuales , Fosfocreatina/metabolismo , Fosfocreatina/sangre , Ceruloplasmina/metabolismo , Cobre/sangre , Cobre/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Magnesio/sangre , Magnesio/metabolismo , Fósforo/sangre , Creatina/metabolismo , Creatina/sangre , Calcio/sangre , Calcio/metabolismo , Estudios de Casos y Controles

RESUMEN

BACKGROUND: Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective. METHODS: We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample. RESULTS: Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6-13.6 µmol/L [n = 45] vs 0.44; 0.24-0.99 µmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1-9.9 µmol/L [n = 8]) and neonatal controls (0.93; 0.4-1.8 µmol/L [n = 784]) (p < 0.05). CONCLUSIONS: We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.

Asunto(s)

Ácido Aspártico , Enfermedad de Canavan , Pruebas con Sangre Seca , Tamizaje Neonatal , Espectrometría de Masas en Tándem , Humanos , Enfermedad de Canavan/diagnóstico , Enfermedad de Canavan/sangre , Enfermedad de Canavan/genética , Recién Nacido , Tamizaje Neonatal/métodos , Pruebas con Sangre Seca/métodos , Espectrometría de Masas en Tándem/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/sangre , Cromatografía Liquida , Femenino , Masculino , Lactante , Preescolar , Cromatografía Líquida con Espectrometría de Masas , Amidohidrolasas

RESUMEN

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia-lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron-deficient substrates is often poor. Here, we report the structure-based engineering of PAL from Planctomyces brasiliensis (PbPAL), enabling preparative-scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide- and ester-containing fumaric acid derivatives. Through the elucidation of cryo-electron microscopy (cryo-EM) PbPAL structure and screening of the structure-based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron-deficient substrates. Our engineered PALs demonstrated exclusive α-regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative-scale hydroamination yielding tert-butyl protected l-aspartic acid, widely used as intermediate in peptide solid-phase synthesis.

Asunto(s)

Ácido Aspártico , Fenilanina Amoníaco-Liasa , Ingeniería de Proteínas , Estereoisomerismo , Ácido Aspártico/química , Ácido Aspártico/análogos & derivados , Fenilanina Amoníaco-Liasa/metabolismo , Fenilanina Amoníaco-Liasa/química , Fenilanina Amoníaco-Liasa/genética , Biocatálisis , Estructura Molecular

RESUMEN

A novel in-tube solid-phase microextraction coupled with an ultra-high performance liquid chromatography-mass spectrometry method has been established for simultaneous quantification of three crucial brain biomarkers N-acetylaspartic acid (NAA), N-acetylglutamic acid (NAG), and N-acetylaspartylglutamic acid (NAAG). A polymer monolith with quaternary ammonium as the functional group was designed and exhibited efficient enrichment of target analytes through strong anion exchange interaction. Under the optimized conditions, the proposed method displayed wide linear ranges (0.1-80 nM for NAA and NAG, 0.2-160 nM for NAAG) with good precision (RSDs were lower than 15%) and low limits of detection (0.019-0.052 nM), which is by far the most sensitive approach for NAA, NAG, and NAAG determination. Furthermore, this approach has been applied to measure the target analytes in mouse brain samples, and endogenous NAA, NAG, and NAAG were successfully detected and quantified from only around 5 mg of cerebral cortex, cerebellum, and hippocampus. Compared with existing methods, the newly developed method in the current study provides highest sensitivity and lowest sample consumption for NAA, NAG, and NAAG measurements, which would potentially be utilized in determining and tracking these meaningful brain biomarkers in diseases or treatment processes, benefiting the investigations of pathophysiology and treatment of brain disorders.

Asunto(s)

Ácido Aspártico , Encéfalo , Dipéptidos , Microextracción en Fase Sólida , Espectrometría de Masas en Tándem , Animales , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análisis , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Ratones , Microextracción en Fase Sólida/métodos , Encéfalo/metabolismo , Dipéptidos/análisis , Límite de Detección , Biomarcadores/análisis , Masculino , Química Encefálica , Glutamatos

RESUMEN

Despite numerous optimizations in peptide synthesis, the formation of aspartimide remains a significant side reaction that needs to be addressed. Herein, we introduce an approach that utilizes hydrazide as a carboxylic-acid-protecting group to reduce the formation of aspartimide. The aspartic acid hydrazide effectively suppressed the formation of aspartimide, even under microwave conditions, and was readily converted to native aspartic acid using CuSO4 in an aqueous medium.

Asunto(s)

Ácido Aspártico , Ácidos Carboxílicos , Péptidos , Técnicas de Síntesis en Fase Sólida , Ácidos Carboxílicos/química , Péptidos/química , Péptidos/síntesis química , Péptidos/farmacología , Estructura Molecular , Ácido Aspártico/química , Ácido Aspártico/análogos & derivados , Microondas , Hidrazinas/química