Potential of Sodium MRI as a Biomarker for Neurodegeneration and Neuroinflammation in Multiple Sclerosis

In multiple sclerosis (MS), experimental and ex vivo studies indicate that pathologic intra- and extracellular sodium accumulation may play a pivotal role in inflammatory as well as neurodegenerative processes. Yet, in vivo assessment of sodium in the microenvironment is hard to achieve. Here, sodium magnetic resonance imaging (23NaMRI) with its non-invasive properties offers a unique opportunity to further elucidate the effects of sodium disequilibrium in MS pathology in vivo in addition to regular proton based MRI. However, unfavorable physical properties and low in vivo concentrations of sodium ions resulting in low signal-to-noise-ratio (SNR) as well as low spatial resolution resulting in partial volume effects limited the application of 23NaMRI. With the recent advent of high-field MRI scanners and more sophisticated sodium MRI acquisition techniques enabling better resolution and higher SNR, 23NaMRI revived. These studies revealed pathologic total sodium concentrations in MS brains now even allowing for the (partial) differentiation of intra- and extracellular sodium accumulation. Within this review we (1) demonstrate the physical basis and imaging techniques of 23NaMRI and (2) analyze the present and future clinical application of 23NaMRI focusing on the field of MS thus highlighting its potential as biomarker for neuroinflammation and -degeneration

Multiparametric MRI for Characterization of the Basal Ganglia and the Midbrain

Objectives To characterize subcortical nuclei by multi-parametric quantitative magnetic resonance imaging.Materials and Methods: The following quantitative multiparametric MR data of five healthy volunteers were acquired on a 7T MRI system: 3D gradient echo (GRE) data for the calculation of quantitative susceptibility maps (QSM), GRE sequences with and without off-resonant magnetic transfer pulse for magnetization transfer ratio (MTR) calculation, a magnetization−prepared 2 rapid acquisition gradient echo sequence for T1 mapping, and (after a coil change) a density-adapted 3D radial pulse sequence for 23Na imaging. First, all data were co-registered to the GRE data, volumes of interest (VOIs) for 21 subcortical structures were drawn manually for each volunteer, and a combined voxel-wise analysis of the four MR contrasts (QSM, MTR, T1, 23Na) in each structure was conducted to assess the quantitative, MR value-based differentiability of structures. Second, a machine learning algorithm based on random forests was trained to automatically classify the groups of multi-parametric voxel values from each VOI according to their association to one of the 21 subcortical structures.Results The analysis of the integrated multimodal visualization of quantitative MR values in each structure yielded a successful classification among nuclei of the ascending reticular activation system (ARAS), the limbic system and the extrapyramidal system, while classification among (epi-)thalamic nuclei was less successful. The machine learning-based approach facilitated quantitative MR value-based structure classification especially in the group of extrapyramidal nuclei and reached an overall accuracy of 85% regarding all selected nuclei.Conclusion Multimodal quantitative MR enabled excellent differentiation of a wide spectrum of subcortical nuclei with reasonable accuracy and may thus enable sensitive detection of disease and nucleus-specific MR-based contrast alterations in the future

First implementation of dynamic oxygen-17 (17O) magnetic resonance imaging at 7 Tesla during neuronal stimulation in the human brain.

OBJECTIVE First implementation of dynamic oxygen-17 (17O) MRI at 7 Tesla (T) during neuronal stimulation in the human brain. METHODS Five healthy volunteers underwent a three-phase 17O gas (17O2) inhalation experiment. Combined right-side visual stimulus and right-hand finger tapping were used to achieve neuronal stimulation in the left cerebral hemisphere. Data analysis included the evaluation of the relative partial volume (PV)-corrected time evolution of absolute 17O water (H217O) concentration and of the relative signal evolution without PV correction. Statistical analysis was performed using a one-tailed paired t test. Blood oxygen level-dependent (BOLD) experiments were performed to validate the stimulation paradigm. RESULTS The BOLD maps showed significant activity in the stimulated left visual and sensorimotor cortex compared to the non-stimulated right side. PV correction of 17O MR data resulted in high signal fluctuations with a noise level of 10% due to small regions of interest (ROI), impeding further quantitative analysis. Statistical evaluation of the relative H217O signal with PV correction (p = 0.168) and without (p = 0.382) did not show significant difference between the stimulated left and non-stimulated right sensorimotor ROI. DISCUSSION The change of cerebral oxygen metabolism induced by sensorimotor and visual stimulation is not large enough to be reliably detected with the current setup and methodology of dynamic 17O MRI at 7 T

First application of dynamic oxygen-17 magnetic resonance imaging at 7 Tesla in a patient with early subacute stroke.

Dynamic oxygen-17 (17O) magnetic resonance imaging (MRI) is an imaging method that enables a direct and non-invasive assessment of cerebral oxygen metabolism and thus potentially the distinction between viable and non-viable tissue employing a three-phase inhalation experiment. The purpose of this investigation was the first application of dynamic 17O MRI at 7 Tesla (T) in a patient with stroke. In this proof-of-concept experiment, dynamic 17O MRI was applied during 17O inhalation in a patient with early subacute stroke. The analysis of the relative 17O water (H217O) signal for the affected stroke region compared to the healthy contralateral side revealed no significant difference. However, the technical feasibility of 17O MRI has been demonstrated paving the way for future investigations in neurovascular diseases

3T vs. 7T fMRI: capturing early human memory consolidation after motor task utilizing the observed higher functional specificity of 7T

ObjectiveFunctional magnetic resonance imaging (fMRI) visualizes brain structures at increasingly higher resolution and better signal-to-noise ratio (SNR) as field strength increases. Yet, mapping the blood oxygen level dependent (BOLD) response to distinct neuronal processes continues to be challenging. Here, we investigated the characteristics of 7 T-fMRI compared to 3 T-fMRI in the human brain beyond the effect of increased SNR and verified the benefits of 7 T-fMRI in the detection of tiny, highly specific modulations of functional connectivity in the resting state following a motor task.Methods18 healthy volunteers underwent two resting state and a stimulus driven measurement using a finger tapping motor task at 3 and 7 T, respectively. The SNR for each field strength was adjusted by targeted voxel size variation to minimize the effect of SNR on the field strength specific outcome. Spatial and temporal characteristics of resting state ICA, network graphs, and motor task related activated areas were compared. Finally, a graph theoretical approach was used to detect resting state modulation subsequent to a simple motor task.ResultsSpatial extensions of resting state ICA and motor task related activated areas were consistent between field strengths, but temporal characteristics varied, indicating that 7 T achieved a higher functional specificity of the BOLD response than 3 T-fMRI. Following the motor task, only 7 T-fMRI enabled the detection of highly specific connectivity modulations representing an “offline replay” of previous motor activation. Modulated connections of the motor cortex were directly linked to brain regions associated with memory consolidation.ConclusionThese findings reveal how memory processing is initiated even after simple motor tasks, and that it begins earlier than previously shown. Thus, the superior capability of 7 T-fMRI to detect subtle functional dynamics promises to improve diagnostics and therapeutic assessment of neurological diseases

A nested eight-channel transmit array with open-face concept for human brain imaging at 7 tesla

Purpose: Parallel transmit technology for MRI at 7 tesla will significantly benefit from high performance transmit arrays that offer high transmit efficiency and low mutual coupling between the individual array elements. A novel dual-mode transmit array with nested array elements has been developed to support imaging the human brain in both the single-channel (sTx) and parallel-transmit (pTx) excitation modes of a 7 tesla MRI scanner. In this work, the design, implementation, validation, specific absorption rate (SAR) management, and performance of the head coil is presented. Methods: The transmit array consisted of a nested arrangement to improve decoupling between the second-neighboring elements. Two large cut-outs were introduced in the RF shield for an open-face design to reduce claustrophobia and to allow patient monitoring. A hardware interface allows the coil to be used in both the sTx and pTx modes. SAR monitoring is done with virtual observation points (VOP) derived from human body models. The transmit efficiency and coverage is compared with the commercial single-channel and parallel-transmit head coils. Results: Decoupling inductors between the second-neighboring coil elements reduced the coupling to less than −20 dB. Local SAR estimates from the electromagnetic (EM) simulations were always less than the EM-based VOPs, which in turn were always less than scanner predictions and measurements for static and dynamic pTx waveforms. In sTx mode, we demonstrate improved coverage of the brain compared to the commercial sTx coil. The transmit efficiency is within 10% of the commercial pTx coil despite the two large cut-outs in the RF shield. In pTx mode, improved signal homogeneity was shown when the Universal Pulse was used for acquisition in vivo. Conclusion: A novel head coil which includes a nested eight-channel transmit array has been presented. The large cut-outs improve patient monitoring and reduce claustrophobia. For pTx mode, the EM simulation and VOP-based SAR management provided greater flexibility to apply pTx methods without the limitations of SAR constraints. For scanning in vivo, the coil was shown to provide an improved coverage in sTx mode compared to a standard commercial head coil

The effects of RF coils and SAR supervision strategies for clinically applicable nonselective parallel-transmit pulses at 7 T

Purpose: To investigate the effects of using different parallel-transmit (pTx) head coils and specific absorption rate (SAR) supervision strategies on pTx pulse design for ultrahigh-field MRI using a 3D-MPRAGE sequence. Methods: The PTx universal pulses (UPs) and fast online-customized (FOCUS) pulses were designed with pre-acquired data sets (B0, B1+ maps, specific absorption rate [SAR] supervision data) from two different 8 transmit/32 receive head coils on two 7T whole-body MR systems. For one coil, the SAR supervision model consisted of per-channel RF power limits. In the other coil, SAR estimations were done with both per-channel RF power limits as well as virtual observation points (VOPs) derived from electromagnetic field (EMF) simulations using three virtual human body models at three different positions. All pulses were made for nonselective excitation and inversion and evaluated on 132 B0, B1+, and SAR supervision datasets obtained with one coil and 12 from the other. At both sites, 3 subjects were examined using MPRAGE sequences that used UP/FOCUS pulses generated for both coils. Results: For some subjects, the UPs underperformed when simulated on a different coil from which they were derived, whereas FOCUS pulses still showed acceptable performance in that case. FOCUS inversion pulses outperformed adiabatic pulses when scaled to the same local SAR level. For the self-built coil, the use of VOPs showed reliable overestimation compared with the ground-truth EMF simulations, predicting about 52% lower local SAR for inversion pulses compared with per-channel power limits. Conclusion: FOCUS inversion pulses offer a low-SAR alternative to adiabatic pulses and benefit from using EMF-based VOPs for SAR estimation

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe