Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

The Impact of MRI-Based Advanced Neuroimaging on Neurooncologists' Clinical Decision-Making in Patients With Posttreatment High-Grade Glioma: A Prospective Survey-Based Study.

Background: Advanced MRI-based neuroimaging techniques, such as perfusion and spectroscopy, have been increasingly incorporated into routine follow-up protocols in patients treated for high-grade glioma (HGG), to help differentiate tumor progression from treatment effect. However, these techniques' influence on clinical management remains poorly understood. Objective: To evaluate the impact of MRI-based advanced neuroimaging on clinical decision-making in patients with HGG in the posttreatment setting. Methods: This prospective study, performed at a comprehensive cancer center from March 1, 2017, to October 31, 2020, included adult patients treated by chemoradiation for WHO grade 4 diffuse glioma who underwent MRIbased advanced neuroimaging (comprising multiple perfusion imaging sequences and spectroscopy) to further evaluate findings on conventional MRI equivocal for tumor progression versus treatment effect. The ordering neuro-oncologists completed surveys before and after each advanced neuroimaging session. The percent of care episodes with a change between the intended and actual management plan on the surveys conducted before and after advanced neuroimaging, respectively, was computed and compared with a previously published percent using the Wald test for independent samples proportions. Results: The study included 63 patients (mean age, 55±13 years; 36 women, 27 men) who underwent 70 advanced neuroimaging sessions. Ordering neuro-oncologists' intended and actual management plans on the surveys completed before and after advanced neuroimaging, respectively, differed in 44% (31/70, [95% CI: 33-56%]) of episodes, which differed from the previously published frequency of 8.5% (5/59) (p<.001). These management plan changes included selection of a different plan for 6/8 episodes with an intended plan to enroll patients in a clinical trial, 12/19 episodes with an intended plan to change chemotherapeutic agents, 4/8 episodes with an intended plan of surgical intervention, and 1/2 episodes with an intended plan of re-irradiation. The ordering neuro-oncologists found advanced neuroimaging to be helpful in 93% (95% CI: 87%-99%) (65/70) of episodes. Conclusion: Neuro-oncologists' management plans changed in a substantial fraction of adult patients with HGG who underwent advanced neuroimaging to further evaluate conventional MRI findings equivocal for tumor progression versus treatment effect. Clinical Impact: The findings support incorporation of advanced neuroimaging into HGG posttreatment monitoring protocols.

The future is 2D: spectral-temporal fitting of dynamic MRS data provides exponential gains in precision over conventional approaches.

PURPOSE: Many MRS paradigms produce 2D spectral-temporal datasets, including diffusion-weighted, functional, and hyperpolarized and enriched (carbon-13, deuterium) experiments. Conventionally, temporal parameters-such as T2 , T1 , or diffusion constants-are assessed by first fitting each spectrum independently and subsequently fitting a temporal model (1D fitting). We investigated whether simultaneously fitting the entire dataset using a single spectral-temporal model (2D fitting) would improve the precision of the relevant temporal parameter. METHODS: We derived a Cramer Rao lower bound for the temporal parameters for both 1D and 2D approaches for 2 experiments: a multi-echo experiment designed to estimate metabolite T2 s, and a functional MRS experiment designed to estimate fractional change ( δ $$ \delta $$ ) in metabolite concentrations. We investigated the dependence of the relative standard deviation (SD) of T2 in multi-echo and δ $$ \delta $$ in functional MRS. RESULTS: When peaks were spectrally distant, 2D fitting improved precision by approximately 20% relative to 1D fitting, regardless of the experiment and other parameter values. These gains increased exponentially as peaks drew closer. Dependence on temporal model parameters was weak to negligible. CONCLUSION: Our results strongly support a 2D approach to MRS fitting where applicable, and particularly in nuclei such as hydrogen and deuterium, which exhibit substantial spectral overlap.

Distinguishing glutamate and glutamine in in vivo 1 H MRS based on nuclear spin singlet order filtering.

PURPOSE: The signals of glutamate (Glu) and glutamine (Gln) are often significantly overlapped in routine 1 H-MR spectra of human brain in vivo. Selectively probing the signals of Glu and Gln in vivo is very important for the study of the metabolisms in which Glu and Gln are involved. METHODS: The Glu-/Gln- targeted pulse sequences are developed to selectively probe the signals of Glu and Gln. The core part of the Glu-/Gln- targeted pulse sequences lies on the preparation of the nuclear spin singlet orders (SSOs) of the five-spin systems of Glu and Gln. The optimal control method is used to prepare the SSOs of Glu and Gln with high efficiency. RESULTS: The Glu-/Gln- targeted pulse sequences have been applied on phantoms to selectively probe the signals of Glu and Gln. Moreover, in the in vivo experiments, the signals of Glu and Gln in human brains of healthy subjects have been successfully probed separately. CONCLUSION: The developed Glu-/Gln- targeted pulse sequences can be used to distinguish the 1 H-MR signals of Glu and Gln in human brains in vivo. The optimal control method provides an effective way to prepare the SSO of a specific spin system with high efficiency and in turn selectively probe the signals of a targeted molecule.

Molecular MRI-Based Monitoring of Cancer Immunotherapy Treatment Response.

Immunotherapy constitutes a paradigm shift in cancer treatment. Its FDA approval for several indications has yielded improved prognosis for cases where traditional therapy has shown limited efficiency. However, many patients still fail to benefit from this treatment modality, and the exact mechanisms responsible for tumor response are unknown. Noninvasive treatment monitoring is crucial for longitudinal tumor characterization and the early detection of non-responders. While various medical imaging techniques can provide a morphological picture of the lesion and its surrounding tissue, a molecular-oriented imaging approach holds the key to unraveling biological effects that occur much earlier in the immunotherapy timeline. Magnetic resonance imaging (MRI) is a highly versatile imaging modality, where the image contrast can be tailored to emphasize a particular biophysical property of interest using advanced engineering of the imaging pipeline. In this review, recent advances in molecular-MRI based cancer immunotherapy monitoring are described. Next, the presentation of the underlying physics, computational, and biological features are complemented by a critical analysis of the results obtained in preclinical and clinical studies. Finally, emerging artificial intelligence (AI)-based strategies to further distill, quantify, and interpret the image-based molecular MRI information are discussed in terms of perspectives for the future.

Relaxation-corrected macromolecular model enables determination of 1 H longitudinal T1 -relaxation times and concentrations of human brain metabolites at 9.4T.

PURPOSE: Ultrahigh field MRS has improved characterization of the neurochemical profile. To compare results obtained at 9.4T to those from lower field strengths, it is of interest to quantify the concentrations of metabolites measured. Thus, measuring T1 -relaxation times is necessary to correct for T1 -weighting that occurs in acquisitions for single-voxel spectroscopy and spectroscopic imaging. A macromolecule (MM) simulation model was developed to fit MM contributions to the short TE inversion series used to measure T1 -relaxation times. METHODS: An inversion series with seven time points was acquired with metabolite-cycled STEAM to estimate T1 -relaxation times of metabolites. A short TE was employed in this study to retain signals from metabolites with short T2 -relaxation times and J-couplings. The underlying macromolecule spectrum was corrected by developing a sequence-specific, relaxation-corrected simulated MM model. Quantification of metabolite peaks was performed using internal water referencing and relaxation corrections. RESULTS: T1 -relaxation times for metabolites range from approximately 750 to approximately 2000 ms and approximately 1000 to approximately 2400 ms in gray matter (GM)- and white matter (WM)- rich voxels, respectively. Quantification of metabolites was compared between GM and WM voxels, as well as between results that used a simulated MM spectrum against those that used an experimentally acquired MM spectrum. Metabolite concentrations are reported in mmol/kg quantities. CONCLUSION: T1 -relaxation times are reported for nonsinglet resonances for the first time at 9.4T by use of a MM simulation model to account for contributions from the MM spectrum. In addition to T1 -relaxation times, quantification results of metabolites from GM- and WM-rich voxels are reported.

In Vivo Brain Glutathione is Higher in Older Age and Correlates with Mobility.

Brain markers of oxidative damage increase with advancing age. In response, brain antioxidant levels may also increase with age, although this has not been well investigated. Here, we used edited magnetic resonance spectroscopy to quantify endogenous levels of glutathione (GSH, one of the most abundant brain antioxidants) in 37 young [mean: 21.8 (2.5) years; 19 female] and 23 older adults [mean: 72.8 (8.9) years; 19 female]. Accounting for age-related atrophy, we identified higher frontal and sensorimotor GSH levels for the older compared with the younger adults. For the older adults only, higher sensorimotor (but not frontal) GSH was correlated with poorer balance and gait. This suggests a regionally specific relationship between higher brain oxidative stress levels and motor performance declines with age. We suggest these findings reflect an upregulation of GSH in response to increasing brain oxidative stress with normal aging. Together, these results provide insight into age differences in brain antioxidant levels and implications for motor function.

Chronic cerebral blood flow alterations in traumatic brain injury and sports-related concussions.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and 1H-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex. RESEARCH DESIGN: Eleven controls, 12 athletes symptomatic following ≥3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery. MAIN OUTCOMES AND RESULTS: RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively. CONCLUSIONS: Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.

Cardiac energetics alteration in a chronic hypoxia rat model: A non-invasive in vivo31P magnetic resonance spectroscopy study.

BACKGROUND: Energetics alteration plays a crucial role in the myocardial injury process in chronic hypoxia diseases (CHD). 31P magnetic resonance spectroscopy (MRS) can investigate alterations in cardiac energetics in vivo. OBJECTIVE: To characterize the potential value of 31P MRS in evaluating cardiac energetics alteration of chronic hypoxic rats (CHRs). METHODS: Twenty-four CHRs were induced by SU5416 combined with hypoxia and divided into four groups according to the modeling time of one, two, three and five weeks, respectively. Control group also contains six rats. 31P MRS was performed weekly and the ratio of concentrations of phosphocreatine (PCr) to adenosine triphosphate (ATP) (PCr/ATP) was obtained. In addition, the cardiac structure index and systolic function parameters, including the right ventricular ejection fraction (RVEF), right ventricular end-diastolic volume index (RVEDVi), right ventricular end-systolic volume index (RVESVi), and the left ventricular function parameters, were measured. RESULTS: Decreased resting cardiac PCr/ATP ratio in CHRs was observed at the first week, compared to the control group (2.90±0.35 vs. 3.31±0.45, p = 0.045), while the RVEF, RVEDVi, and RVESVi decreased at the second week (p < 0.05). The PCr/ATP ratio displayed a significant correlation with RVEF (r = 0.605, p = 0.001), RVEDVi, and RVESVi (r = -0.661, r = -0.703; p < 0.001). CONCLUSIONS: 31P MRS can easily detect the cardiac energetics alteration in a CHR model before the onset of ventricular dysfunction. The decreased PCr/ATP ratio likely reveales myocardial injury and cardiac dysfunction.

Evaluation of 3T proton MR spectroscopy in the spinal cord - preliminary results.

Purpose: 1H-magnetic resonance spectroscopy (1H-MRS) is a non-invasive technique that provides information on tissue metabolism and biochemistry. Because of technical difficulties, this method is rarely used in spinal cord examination. The main goal of this study was to develop a routine protocol for MRS of intramedullary lesions. Material and methods: A 1H-MRS protocol was set on a group of healthy volunteers. Forty-eight spectra were acquired in total. Thirty of them were acquired in cervical spinal cord, and the remaining 18 spectra were acquired in the thoracic spinal cord. Results: In 1H-MRS of the spinal cord one of the most important problems is small voxel size. Mean voxel size in this study was 7 × 9 × 29 mm, which is much smaller than in brain examinations. Finally, almost 60% of spectra were of acceptable quality in volunteer examinations, which enabled the subsequent examinations. Conclusions: Challenges of spinal cord spectroscopy were discussed, and the ability of providing additional diagnostic information was proven.

Frequency drift in MR spectroscopy at 3T.

PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Transcranial magnetic stimulation and magnetic resonance spectroscopy: Opportunities for a bimodal approach in human neuroscience.

Over the last decade, there has been an increasing number of studies combining transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). MRS provides a manner to non-invasively investigate molecular concentrations in the living brain and thus identify metabolites involved in physiological and pathological processes. Particularly the MRS-detectable metabolites glutamate, the major excitatory neurotransmitter, and gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, are of interest when combining TMS and MRS. TMS is a non-invasive brain stimulation technique that can be applied either as a neuromodulation or neurostimulation tool, specifically targeting glutamatergic and GABAergic mechanisms. The combination of TMS and MRS can be used to evaluate alterations in brain metabolite levels following an interventional TMS protocol such as repetitive TMS (rTMS) or paired associative stimulation (PAS). MRS can also be combined with a variety of non-interventional TMS protocols to identify the interplay between brain metabolite levels and measures of excitability or receptor-mediated inhibition and facilitation. In this review, we provide an overview of studies performed in healthy and patient populations combining MRS and TMS, both as a measurement tool and as an intervention. TMS and MRS may reveal complementary and comprehensive information on glutamatergic and GABAergic neurotransmission. Potentially, connectivity changes and dedicated network interactions can be probed using the combined TMS-MRS approach. Considering the ongoing technical developments in both fields, combined studies hold future promise for investigations of brain network interactions and neurotransmission.

Multivariate approach for longitudinal analysis of brain metabolite levels from ages 5-11 years in children with perinatal HIV infection.

Treatment guidelines recommend that children with perinatal HIV infection (PHIV) initiate antiretroviral therapy (ART) early in life and remain on it lifelong. As part of a longitudinal study examining the long-term consequences of PHIV and early ART on the developing brain, 89 PHIV children and a control group of 85 HIV uninfected children (HIV-) received neuroimaging at ages 5, 7, 9 and 11 years, including single voxel magnetic resonance spectroscopy (MRS) in three brain regions, namely the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM). We analysed age-related changes in absolute metabolite concentrations using a multivariate approach traditionally applied to ecological data, the Correlated Response Model (CRM) and compared these to results obtained from a multilevel mixed effect modelling (MMEM) approach. Both approaches produce similar outcomes in relation to HIV status and age effects on longitudinal trajectories. Both methods found similar age-related increases in both PHIV and HIV- children in almost all metabolites across regions. We found significantly elevated GPC+PCh across regions (95% CI=[0.033; 0.105] in BG; 95% CI=[0.021; 0.099] in PWM; 95% CI=[0.059; 0.137] in MFGM) and elevated mI in MFGM (95% CI=[0.131; 0.407]) among children living with PHIV compared to HIV- children; additionally the CRM model also indicated elevated mI in BG (95% CI=[0.008; 0.248]). These findings suggest persistent inflammation across the brain in young children living with HIV despite early ART initiation.

On the functional role of striatal and anterior cingulate GABA+ in stimulus-response binding.

Successful response selection relies on constantly updating stimulus-response associations. The Theory of Event Coding (TEC) proposes that perception and action are conjointly coded in event files, for which fronto-striatal networks seem to play an important role. However, the exact neurobiochemical mechanism behind event file coding has remained unknown. We investigated the functional relevance of the striatal and anterior cingulate (ACC) GABAergic system using magnetic resonance spectroscopy (MRS). Specifically, the striatal and ACC concentrations of GABA+ referenced against N-acetylaspartate (NAA) were assessed in 35 young healthy males, who subsequently performed a standard event file task. As predicted by the TEC, the participants' responses were modulated by pre-established stimulus response bindings in event files. GABA+/NAA concentrations in the striatum and ACC were not correlated with the overall event binding effect. However, higher GABA+/NAA concentrations in the ACC were correlated with stronger event file binding processes in the early phase of the task. This association disappeared by the end of the task. Taken together, our findings show that striatal GABA+ levels does not seem to modulate event file binding, while ACC GABA+ seem to improve event file binding, but only as long as the participants have not yet gathered sufficient task experience. To the best of our knowledge, this is the first study providing direct evidence for the role of striatal and ACC GABA+ in stimulus-response bindings and thus insights into the brain structure-specific neurobiological aspects of the TEC.

Neurochemical properties measured by 1H magnetic resonance spectroscopy may predict cognitive behaviour therapy outcome in paediatric OCD: a pilot study.

To identify neurochemical factors measured pre-treatment that may predict cognitive behavioural treatment (CBT) outcome, aiming at understanding possible causes of poor CBT response. 1H magnetic resonance spectroscopy was used before treatment with CBT in treatment naïve 11-18 year-old patients with moderate-severe OCD. Diagnoses and assessment of OCD severity were based on semi-structured interviews. Linear mixed effects models were used to analyse the association between metabolite level and treatment outcome. Worse CBT outcome was associated with higher concentration of glutamine and glutamate combined (Glx) in middle cingulate cortex (MCC) (F = + 3.35, p = 0.004) and of N-acetylaspartate and N-acetylaspartylglutamate combined (tNAA) (F = + 2.59, p = 0.019). Also, we noted a tendency towards higher thalamic Glx concentration (F = + 1.91, p = 0.077) to be associated with worse CBT outcome. In general, the findings of the current pilot study are compatible with the hypothesis of an overweight of excitatory to inhibitory factors in brain circuits driving goal-directed behaviours (GDB). Higher MCC Glx and tNAA may be involved in the selection of GDB. A more detailed understanding of how these brain areas function in health and illness is needed.

Intra-tumoural lipid composition and lymphovascular invasion in breast cancer via non-invasive magnetic resonance spectroscopy.

OBJECTIVES: Despite improved survival due to new treatments, the 10-year survival rate in patients with breast cancer is approximately 75%. Lymphovascular invasion (LVI), a prognostic marker independent from histological grade and stage, can only be fully determined at final histological examination. Lipid composition is deregulated in tumour via de novo lipogenesis, with alteration in lipogenic genes in LVI. We hypothesise alteration in lipid composition derived from novel non-invasive spectroscopy method is associated with LVI positivity. METHODS: Thirty female patients (age 39-78) with invasive ductal carcinoma were enrolled, with 13 LVI negative and 17 LVI positive. Saturated, monounsaturated, polyunsaturated fatty acids and triglycerides (SFA, MUFA, PUFA and TRG) were quantified from ex vivo breast tumours freshly excised from patients on a 3 T clinical MRI scanner, and proliferative activity marker Ki-67 and serotonin derived histologically. RESULTS: There were significantly lower MUFA (p = 0.0189) in LVI positive (median: 0.37, interquartile range (IQR): 0.25-0.64) than negative (0.63, 0.49-0.96). There were significantly lower TRG (p = 0.0226) in LVI positive (1.32, 0.95-2.43) than negative (2.5, 1.92-4.15). There was no significant difference in SFA (p = 0.6009) or PUFA (p = 0.1641). There was no significant correlation between lipid composition against Ki-67 or serotonin, apart from a borderline negative correlation between PUFA and serotonin (r = - 0.3616, p = 0.0496). CONCLUSION: Lipid composition might provide a biomarker to study lymphovascular invasion in breast cancer. KEY POINTS: • Monounsaturated fatty acids in lymphovascular invasion (LVI) positive invasive breast carcinoma were significantly lower than that in LVI negative. • Triglycerides in LVI positive invasive breast carcinoma were significantly lower than that in LVI negative. • Lipid composition from MR spectroscopy reflects the rate of de novo lipogenesis and provides a potential biomarker independent from histological grade and stage.

3T MEGA-PRESS study of N-acetyl aspartyl glutamate and N-acetyl aspartate in activated visual cortex.

OBJECTIVE: To measure N-acetyl aspartyl glutamate (NAAG) and N-acetyl aspartate (NAA) concentrations in visual cortex activated by a continuous stimulation in a 3 T field. METHODS: NAAG and NAA spectra were obtained with MEGA-PRESS pulse sequence (TE/TR = 140/2000 ms; δONNAAG/δOFFNAAG = 4.61/4.15 ppm; δONNAA/δOFFNAA = 4.84/4.38 ppm) in 14 healthy volunteers at rest and upon stimulation by a radial checkerboard flickering at a frequency of 8 Hz. Spectra of all subjects were frequency and phase aligned and then averaged. Additionally, to obtain the time-dependency data, spectra were divided into time sections of 64 s each. The intensities of NAA, NAAG and lactate + macromolecular (Lac + MM) signals were defined by integration of the real part of spectra. The heights of the central resonance of NAAG and NAA signals were measured. RESULTS: The NAAG and NAA concentrations, measured with 2.5% and 0.5% error, respectively, were unaffected by visual activation. A significant increase in the Lac + MM signal by ~ 12% is clearly observed. No stimulation-induced time dependency was found for NAAG or NAA, while the increase in Lac + MM was gradual. The concentration values in visual cortex are in good agreement with the 7 T MRS measurements: [NAAG] = 1.55 mM, [NAA] = 11.95 mM. CONCLUSION: The MEGA-PRESS pulse sequence together with the spectral preprocessing techniques allowed to demonstrate that the concentrations of NAAG and NAA in the visual cortex remain constant during continuous visual stimulation within the margin of error. An increase in the lactate signal intensity signifies the activation of the anaerobic glycolysis in activated visual cortex.

Myocardial inflammation and energetics by cardiac MRI: a review of emerging techniques.

The role of inflammation in cardiovascular pathophysiology has gained a lot of research interest in recent years. Cardiovascular Magnetic Resonance has been a powerful tool in the non-invasive assessment of inflammation in several conditions. More recently, Ultrasmall superparamagnetic particles of iron oxide have been successfully used to evaluate macrophage activity and subsequently inflammation on a cellular level. Current evidence from research studies provides encouraging data and confirms that this evolving method can potentially have a huge impact on clinical practice as it can be used in the diagnosis and management of very common conditions such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathy, myocarditis and atherosclerosis. Another important emerging concept is that of myocardial energetics. With the use of phosphorus magnetic resonance spectroscopy, myocardial energetic compromise has been proved to be an important feature in the pathophysiological process of several conditions including diabetic cardiomyopathy, inherited cardiomyopathies, valvular heart disease and cardiac transplant rejection. This unique tool is therefore being utilized to assess metabolic alterations in a wide range of cardiovascular diseases. This review systematically examines these state-of-the-art methods in detail and provides an insight into the mechanisms of action and the clinical implications of their use.

The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis.

The appearance of new disease-modifying therapies in multiple sclerosis (MS) has revolutionized our ability to fight inflammatory relapses and has immensely improved patients' quality of life. Although remarkable, this achievement has not carried over into reducing long-term disability. In MS, clinical disability progression can continue relentlessly irrespective of acute inflammation. This "silent" disease progression is the main contributor to long-term clinical disability in MS and results from chronic inflammation, neurodegeneration, and repair failure. Investigating silent disease progression and its underlying mechanisms is a challenge. Standard MRI excels in depicting acute inflammation but lacks the pathophysiological lens required for a more targeted exploration of molecular-based processes. Novel modalities that utilize nuclear magnetic resonance's ability to display in vivo information on imaging look to bridge this gap. Displaying the CNS through a molecular prism is becoming an undeniable reality. This review will focus on "molecular imaging biomarkers" of disease progression, modalities that can harmoniously depict anatomy and pathophysiology, making them attractive candidates to become the first valid biomarkers of neuroprotection and remyelination.

Brain mitochondrial impairment in early-onset Parkinson's disease with or without PINK1 mutation.

BACKGROUND: PINK1 mutations are likely to affect mitochondrial function. The objective of this study was to study brain mitochondrial function in patients with early-onset Parkinson's disease, with or without PINK1 mutations. METHODS: We investigated brain intracellular pH, mitochondrial activity, and energetics with functional magnetic resonance spectroscopy in patients with early-onset Parkinson's disease with PINK1 mutations (n = 10), early-onset Parkinson's disease without PINK1 mutations (n = 10), and healthy sex- and age-matched subjects (n = 20). We measured peak areas of phosphocreatine and beta adenosine triphosphate. RESULTS: The EOPD- group had normal PCr + ßATP contents at rest (P = NS) and under activation (P = NS), but reduced contents during recovery (P < 0.001). The EOPD+ group had abnormal PCr + ßATP contents at rest (P < 0.001) and during activation (P < 0.001); during recovery, the contents only partially recovered (P < 0.001). Brain intracellular pH alterations were more severe with EOPD+ than with EOPD-. CONCLUSIONS: Brain mitochondrial impairments were similar in early-onset Parkinson's disease without PINK1 mutations and late-onset Parkinson's disease. However, mitochondrial impairments were more severe in early-onset Parkinson's disease with PINK1 mutations. © 2020 International Parkinson and Movement Disorder Society.