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Examples of quality of spectra obtained over the whole brain using the 3D-1 H-EPSI sequence (male, 31 years old). The horizontal scale is shown in ppm.
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Background:
Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet.
Objective:
To determine in vivo the metabolic counterpart of brain sodium accumulation.
Materials/methods:
Whole brain (23)Na-MR imaging and 3D-(1)H-EPSI data were collected in 21 re...
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Aim:
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Citations
... These include iron-sensitive MRI sequences that can detect rims of microglia activation around chronic lesions 36,37 ; the detection of cortical lesions 38 ; and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) imaging of leptomeningeal inflammation that may reflect cortical demyelination. 39 Other research methods that may further characterize CNS pathology include PET imaging using radioligands specific to activated microglia and astroycytes, such as 18-kDa translocator protein (TSPO) 40 ; magnetic transfer imaging (MTI) to evaluate myelin content 41 ; magnetic resonance spectroscopy (MRS) to evaluate metabolic changes associated with neuroaxonal loss and mitochondrial dysfunction 42 ; and diffusion tensor imaging, which examines microstructural changes, including axonal and myelin loss in the brain and spinal cord. 43 Although most of these techniques have demonstrated robust correlations with clinical disability in pwMS, a major hurdle preventing their widespread use in clinical practice is the lack of access to necessary sequences, software for image processing, determining clinically-relevant thresholds, and integration into the clinical workflow. ...
Significant advances have been made in the diagnosis and treatment of multiple sclerosis in recent years yet challenges remain. The current classification of MS phenotypes according to disease activity and progression, for example, does not adequately reflect the underlying pathophysiological mechanisms that may be acting in an individual with MS at different time points. Thus, there is a need for clinicians to transition to a management approach based on the underlying pathophysiological mechanisms that drive disability in MS. A Canadian expert panel convened in January 2023 to discuss priorities for clinical discovery and scientific exploration that would help advance the field. Five key areas of focus included: identifying a mechanism-based disease classification system; developing biomarkers (imaging, fluid, digital) to identify pathologic processes; implementing a data-driven approach to integrate genetic/environmental risk factors, clinical findings, imaging and biomarker data, and patient-reported outcomes to better characterize the many factors associated with disability progression; utilizing precision-based treatment strategies to target different disease processes; and potentially preventing disease through Epstein-Barr virus (EBV) vaccination, counselling about environmental risk factors (e.g. obesity, exercise, vitamin D/sun exposure, smoking) and other measures. Many of the tools needed to meet these needs are currently available. Further work is required to validate emerging biomarkers and tailor treatment strategies to the needs of individual patients. The hope is that a more complete view of the individual’s pathobiology will enable clinicians to usher in an era of truly personalized medicine, in which more informed treatment decisions throughout the disease course achieve better long-term outcomes.
... This supports the notion that TSC accumulation reflects not only the expansion of extracellular space due to demyelination and neuroaxonal loss, but also metabolic dysfunction. Concurrent ionic and metabolic mapping at 3 T confirmed that the observed sodium accumulations in MS are related to mitochondrial neuronal dysfunction, thus highlighting the role of energy failure in MS [224]. ...
... An observational study by Huhn et al., provided data that increased the importance of skin as sodium storage and concluded that these results may further present skin for future research on salt as a pro-inflammatory agent driving autoimmune neuritis, such as in multiple sclerosis [82]. According to researchers, longitudinal studies are necessary to determine whether an increase in sodium content in the skin precedes the development of MS or is a consequence of the disease [83,84]. ...
Purpose:
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system in which multifocal damage to the brain and spinal cord occurs. The etiology of MS remains unclear but it is often recognized by researchers as a multifactorial disease that involves autoimmune and genetic predisposition combined with environmental influences (e.g., low vitamin D levels, smoking, obesity). An adequate and balanced diet can be extremely helpful in improving the condition of MS patients, effectively supporting pharmacological therapy. The purpose of the study was to investigate whether, and if so, to what extent, the intake of macronutrients, vitamins, and microelements may affect the course of MS.
Views:
The review presents data from studies published between 2017 and 2022.
Conclusions:
There are numerous studies on the role of specific dietary components in the treatment of MS, but the results are still limited. More work is needed to define the tools required for the assessment of patients' eating habits because dietary factors can affect the functioning and quality of life of MS patients and should therefore be evaluated to assist in comprehensive treatment and recovery.
... 100 With 23 Na MRI, TSC was elevated in the brains of AD patients, 101 in the brains of HD patients, 102 and in both the brains and spinal cords of MS patients. [103][104][105] In particular, sodium accumulation in the gray matter of MS patients was associated with impaired cognition, 106 dysfunctional mitochondria, 107 and compromised spinal cord tissue integrity (reduced fractional anisotropy). 104 including diabetes mellitus, fatty liver disease, and chronic kidney disease (CKD), among others. ...
Clinical medicine has experienced a rapid development in the past decades where therapies targeting specific cellular signaling pathways, or specific cell surface receptors, are being increasingly adopted. While these developments in clinical medicine call for improved precision in diagnosis and treatment monitoring, modern medical imaging methods are restricted mainly to anatomical imaging, lagging behind the requirements of precision medicine. Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used clinically for metabolism study, their applications have been limited by the exposure risk to ionizing radiation, the subsequent limitation in repeated and longitudinal studies, and the incapability in assessing downstream metabolism. Magnetic resonance spectroscopy (MRS) or spectroscopic imaging (MRSI) are, in theory, capable of assessing molecular activities in vivo, although often limited by sensitivity. Here we review some recent developments in MRS and MRSI of multiple nuclei that have potential as molecular imaging tools in the clinic.
... Furthermore, it has been hypothesized that the observed increase in TSC would mainly reflect energetic failures due to mitochondrial dysfunction affecting the Na + /K + pump activity (Ridley, Marchi, et al., 2017;Stys et al., 1992). Thus, measuring both sodium and NAA in the same regions provides clues with regard to the mitochondrial defect hypothesis (Donadieu et al., 2019;Paling et al., 2011). However, the use of this metabolite has been limited by poor resolution and spatial coverage of routinely performed 1 H-MRSI, as well as by its insufficient specificity. ...
... ROI selection process is detailed in the next paragraph. The maps that we used for the ROIs signal extraction are the average maps of realigned AC-PC and AC-PC 15 oriented maps(Donadieu et al., 2019;Lecocq et al., 2015) (SPM12; Statistical Parametric Mapping: The Analysis of Functional Brain Images -1st Edition, n.d.). ...
Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. We combined sodium MRI (23 Na MRI) and 1 H-MR Spectroscopic Imaging (1 H-MRSI), assessing changes within epileptogenic networks in comparison with electrophysiologically normal networks as defined by stereotactic EEG (SEEG) recordings analysis. We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7 T (23 Na-MRI) and a 3D echo-planar spectroscopic imaging sequence at 3 T (1 H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23 Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated with the short component of T2 * decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho), and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls. Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients' propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients' regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ. Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.
... In contrast to that, tNAA and mIns clearly showed changes of high magnitude on single metabolite maps, which was also shown in previous MRS studies. 23,56,57 Taking the ratio of tNAA or mIns to tCr might have led to an underestimation of the respective metabolic changes, although still remaining clearly distinguishable. ...
Background
Magnetic resonance spectroscopic imaging (MRSI) of the brain enables in vivo assessment of metabolic alterations in multiple sclerosis (MS). This provides complementary insights into lesion pathology that cannot be obtained via T1- and T2-weighted conventional magnetic resonance imaging (cMRI).
Purpose
The aims of this study were to assess focal metabolic alterations inside and at the periphery of lesions that are visible or invisible on cMRI, and to correlate their metabolic changes with T1 hypointensity and the distance of lesions to cortical gray matter (GM).
Methods
A 7 T MRSI was performed on 51 patients with relapsing-remitting MS (30 female/21 male; mean age, 35.4 ± 9.9 years). Mean metabolic ratios were calculated for segmented regions of interest (ROIs) of normal-appearing white matter, white matter lesions, and focal regions of increased mIns/tNAA invisible on cMRI. A subgroup analysis was performed after subdividing based on T1 relaxation and distance to cortical GM. Metabolite ratios were correlated with T1 and compared between different layers around cMRI-visible lesions.
Results
Focal regions of, on average, 2.8-fold higher mIns/tNAA than surrounding normal-appearing white matter and with an appearance similar to that of MS lesions were found, which were not visible on cMRI (ie, ~4% of metabolic hotspots). T1 relaxation was positively correlated with mIns/tNAA (P ≤ 0.01), and negatively with tNAA/tCr (P ≤ 0.01) and tCho/tCr (P ≤ 0.01). mIns/tCr was increased outside lesions, whereas tNAA/tCr distributions resembled macroscopic tissue damage inside the lesions. mIns/tCr was −21% lower for lesions closer to cortical GM (P ≤ 0.05).
Conclusions
7 T MRSI allows in vivo visualization of focal MS pathology not visible on cMRI and the assessment of metabolite levels in the lesion center, in the active lesion periphery and in cortical lesions. This demonstrated the potential of MRSI to image mIns as an early biomarker in lesion development.
... It is noteworthy that patients are sparse from the presence of GMSA when they are both sparse form physical and cognitive disability, but that the extent of GM involved by sodium abnormalities is not different. This result suggests that it is the presence of GMSA, regardless of its extension, that is associated with clinical disability and possibly on-going neurodegenerative processes [24]. Sodium imaging does not provide a direct structural information of the brain but provides a functional information of the dynamic ionic changes that may occur (in both ways, increase and decrease) [25]. ...
Objective
Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS).
Methods
We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent ²³ Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis.
Results
In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) ( p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration ( n = 7) from the BMS group (OR = 4.6).
Conclusion
Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.
... MS is the most common nontraumatic neurological disease, which is marked by acute and chronic inflammation, demyelination, and neurodegeneration. It is accountable for irrevocable disability in young adults 81,95 and is characterized by demyelination and neuronal injury caused by diffuse and focal inflammation of the GM and WM. 81 Chronically demyelinated axons are susceptible to trophic failure and degeneration due to increased energy demand. ...
... 66 Sodium accumulation is suggested to be the major rationale behind this neurodegenerative process, which potentially acts as a relevant marker for MS. 95,97 By determining an increase in TSC, 23 Na MRI can be used for therapeutic interventions as they help indicate the axonal dysfunction, which can generate insights way before the occurrence of irreversible axonal damage. 43 Studies on relapsing−remitting MS have demonstrated elevated TSC, especially in the normal-appearing brain tissues. ...
... 81,85 Also, lower glutamate− glutamine (Glx) and choline levels have been observed in the GM of patients along with lower N-acetyl aspartate (NAA) and Glx levels with higher myo-inositol in NAWM, which indicate neuronal mitochondrial dysfunction. 95 An increased level of TSC in NAWM and GM has also been reported in cognitively impaired patients as compared to healthy controls and cognitively preserved patients. 98 This proposes that sodium accumulation is highly associated with cognitive impairment. ...
... 12,17,18 While useful, single-voxel techniques require a-priori selection of the brain region to be imaged, and contributions from surrounding areas are not assessed. Whole-brain MRSI studies are able to overcome this restriction, but those conducted in MS to date have typically restricted analyses to whole-brain white matter or lesions 19,20 rather than the entire brain. ...
... 21,[35][36][37] Our findings of reduced NAA/CR in widespread brain regions in the older MS group are consistent with the emerging evidence regarding gray matter pathology in MS, which has been demonstrated using both conventional MRI [38][39][40] as well as MRS. 20,41 Gray matter pathology may be a result of demyelination, may precede white matter abnormalities, or both. NAA/CR decreases in the right thalamus are particularly notable because this was the only result to survive corrections for multiple comparisons in our sample, and is consistent with prior studies that have demonstrated thalamic NAA reductions. ...
Background
Older adults with multiple sclerosis (MS) experience mobility impairments, but conventional brain imaging is a poor predictor of walking abilities in this population.
Objective
To test whether brain metabolites measured with Magnetic Resonance Spectroscopy (MRS) are associated with walking performance in older adults with MS.
Methods
Fifteen older adults with MS (mean age: 60.9, SD: 5.1) and 22 age-matched healthy controls (mean age: 64.2, SD: 5.7) underwent whole-brain MRS and mobility testing. Levels of N-acetylaspartate (NAA), myo-inositol (MI), choline (CHO), and temperature in 47 brain regions were compared between groups and correlated with walking speed (Timed 25 Foot Walk) and walking endurance (Six-Minute Walk).
Results
Older adults with MS had higher MI in 23 areas, including the bilateral frontal (right: t (21.449) = −2.605, P = .016; left: t (35) = −2.434, P = .020), temporal (right: t (35) = −3.063, P = .004; left: t (35) = −3.026, P = .005), and parietal lobes (right: t (21.100) = −2.886, P = .009; left: t (35) = −2.507, P = .017), and right thalamus (t (35) = −2.840, P = .007). MI in eleven regions correlated with walking speed, and MI in twelve regions correlated with walking endurance. NAA was lower in MS in the bilateral thalami (right: t (35) = 3.449, P < .001; left: t (35) = 2.061, P = .047), caudate nuclei (right: t (33) = 2.828, P = .008; left: t (32) = 2.132, P = .041), and posterior cingulum (right: t (35) = 3.077, P = .004; left: t (35) = 2.972, P = .005). NAA in four regions correlated with walking speed and endurance. Brain temperature was higher in MS patients in four regions, but did not correlate with mobility measures. There were no group differences in CHO.
Conclusion
MI and NAA may be useful imaging end-points for walking ability as a clinical outcome in older adults with MS.
... Sodium MRI (NaMRI) has been applied to the study of multiple sclerosis (MS) for a decade and nearly all studies have focused on sodium density-weighted (NaDW) methods and tissue sodium concentration (TSC) measurement (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). However, the underlying microstructural or metabolic sources of the reported range of 20-80% greater TSC in lesions and 5-39% greater TSC in Normal Appearing White Matter (NAWM) remain unclear. ...
Introduction: The source of Tissue Sodium Concentration (TSC) increase in Multiple Sclerosis (MS) remains unclear, and could be attributed to altered intracellular sodium concentration or tissue microstructure. This paper investigates sodium in MS using three new MRI sequences.
Methods: Three sodium scans were acquired at 4.7 T from 30 patients (11 relapsing-remitting, 10 secondary-progressive, 9 primary-progressive) and 9 healthy controls including: Density-Weighted (NaDW), with very short 30° excitation for more accurate TSC measurement; Projection Acquisition with Coherent MAgNetization (NaPACMAN), designed for enhanced relaxation-based contrast; and Soft Inversion Recovery FLuid Attenuation (NaSIRFLA), developed to reduce fluid space contribution. Signal was measured in both lesions (n = 397) and normal appearing white matter (NAWM) relative to controls in the splenium of corpus callosum and the anterior and posterior limbs of internal capsule. Correlations with clinical and cognitive evaluations were tested over all MS patients.
Results: Sodium intensity in MS lesions was elevated over control WM by a greater amount for NaPACMAN (75%) than NaDW (35%), the latter representing TSC. In contrast, NaSIRFLA exhibited lower intensity, but only for region specific analysis in the SCC (−7%). Sodium intensity in average MS NAWM was not significantly different than control WM for either of the three scans. NaSIRFLA in the average NAWM and specifically the posterior limb of internal capsules positively correlated with the Paced Auditory Serial Addition Test (PASAT).
Discussion: Lower NaSIRFLA signal in lesions and ~2× greater NaPACMAN signal elevation over control WM than NaDW can be explained with a demyelination model that also includes edema. A NAWM demyelination model that includes tissue atrophy suggests no signal change for NaSIRFLA, and only slightly greater NAWM signal than control WM for both NaDW and NaPACMAN, reflecting experimental results. Models were derived from previous total and myelin water fraction study in MS with T2-relaxometry, and for the first time include sodium within the myelin water space. Reduced auditory processing association with lower signal on NaSIRFLA cannot be explained by greater demyelination and its modeled impact on the three sodium MRI sequences. Alternative explanations include intra- or extracellular sodium concentration change. Relaxation-weighted sodium MRI in combination with sodium-density MRI may help elucidate microstructural and metabolic changes in MS.
