Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms.Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS.Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS.Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS.Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted.

Quantitative magnetisation transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis.

Myelin-sensitive MRI such as magnetisation transfer imaging has been widely used in the clinical context of multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we aim to review systematically the use of quantitative magnetisation transfer imaging in the brain in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetisation transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including "magnetisation transfer" and "brain" for systematic review. Only studies which used human in vivo quantitative magnetisation transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Data including sample size, magnetic field strength, MRI acquisition protocol parameters, treatments and clinical findings were extracted. Where possible, effect sizes were calculated for meta-analyses to determine magnetisation transfer (1) differences between patients and healthy controls; (2) longitudinal change; and, (3) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met the inclusion/exclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined MTR (magnetisation transfer ratio) in white matter, but magnetisation transfer metrics, brain regions and results were heterogeneous. Analysis demonstrated a risk of bias due to selective reporting and small sample sizes. A random-effects meta-analysis revealed MTR was 1.1 percent units [95% CI -1.47pu to -0.73pu] lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: -6.04, p<0.001, n=23). Linear mixed-model analysis did not show a significant longitudinal change in MTR across all brain regions (β=-0.14 [-0.9 to 0.61], t-value=-0.38, p=0.71, n=13) or normal-appearing white matter alone (β=-0.082 [-0.13 to -0.29], t-value=0.78, p=0.44, n=7). There was a significant negative association between MTR and clinical disability, as assessed by the Expanded Disability Status Scale (r=-0.30 [95% CI -0.48 to -0.08]; z-value=-2.91, p=0.01, n=8). Evidence suggests that magnetisation transfer imaging is sensitive to pathological changes in relapsing-remitting multiple sclerosis, although the effect of relapsing-remitting multiple sclerosis on magnetisation transfer metrics in different brain tissue types was small in comparison to the inter-study variability. Recommended improvements include: the use of techniques such as MTsat (magnetisation transfer saturation) or ihMTR (inhomogeneous MTR) which provide more robust and specific microstructural measures within clinically feasible acquisition times; detailed methodological reporting standards; and larger, demographically diverse cohorts for comparison, including healthy controls.

An in vivo Probabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson’s disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent with post mortem findings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structure in vivo at high-resolution (resolution 0.4×0.4×0.5 mm, duration seven minutes). Magnetisation transfer images from 53 healthy older volunteers (52-84 years) revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults, appropriate for clinical research. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance differences of the LC were observed, mirroring distinctive ex vivo spatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset is available for researchers, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.

Optimisation of pyruvate hyperpolarisation using SABRE by tuning the active magnetisation transfer catalyst

SABRE catalysts [Ir(H)2(η2-pyruvate)(sulfoxide)(NCH) transfer magnetisation from para-hydrogen to pyruvate yielding hyperpolarised 13C NMR signals enhanced by >2000-fold. Properties of the catalyst control efficiency.

The potential of magnetisation transfer NMR to monitor the dissolution process of cellulose in cold alkali

Cellulose is the most important biopolymer on earth and, when derived from e.g. wood, a promising alternative to for example cotton, which exhibits a large environmental burden. The replacement depends, however, on an efficient dissolution process of cellulose. Cold aqueous alkali systems are attractive but these solvents have peculiarities, which might be overcome by understanding the acting mechanisms. Proposed dissolution mechanisms are for example the breakage of hydrophobic interactions and partly deprotonation of the cellulose hydroxyl groups. Here, we performed a mechanistic study using equimolar aqueous solutions of LiOH, NaOH and KOH to elucidate the dissolution process of microcrystalline cellulose (MCC). The pH was the highest for KOH(aq) followed by NaOH(aq) and LiOH(aq). We used a combination of conventional and advanced solution-state NMR methods to monitor the dissolution process of MCC by solely increasing the temperature from − 10 to 5 °C. KOH(aq) dissolved roughly 25% of the maximum amount of MCC while NaOH(aq) and LiOH(aq) dissolved up to 70%. Water motions on nanoscale timescales present in non-frozen water, remained unaffected on the addition of MCC. Magnetisation transfer (MT) NMR experiments monitored the semi-rigid MCC as a function of temperature. Interestingly, although NaOH(aq) and LiOH(aq) were able to dissolve a similar amount at 5 °C, MT spectra revealed differences with increasing temperature, suggesting a difference in the swollen state of MCC in LiOH(aq) already at − 10 °C. Furthermore, MT NMR shows a great potential to study the water exchange dynamics with the swollen and semi-rigid MCC fraction in these systems, which might give valuable insights into the dissolution mechanism in cold alkali.

Periventricular magnetisation transfer ratio abnormalities in multiple sclerosis improve after alemtuzumab

Background: In multiple sclerosis (MS), disease effects on magnetisation transfer ratio (MTR) increase towards the ventricles. This periventricular gradient is evident shortly after first symptoms and is independent of white matter lesions. Objective: To explore if alemtuzumab, a peripherally acting disease-modifying treatment, modifies the gradient’s evolution, and whether baseline gradients predict on-treatment relapses. Methods: Thirty-four people with relapsing-remitting MS underwent annual magnetic resonance imaging (MRI) scanning (19 receiving alemtuzumab (four scans each), 15 untreated (three scans each)). The normal-appearing white matter was segmented into concentric bands. Gradients were measured over the three bands nearest the ventricles. Mixed-effects models adjusted for age, gender, relapse rate, lesion number and brain parenchymal fraction compared the groups’ baseline gradients and evolution. Results: Untreated, the mean MTR gradient increased (+0.030 pu/band/year) but decreased following alemtuzumab (−0.045 pu/band/year, p = 0.037). Within the alemtuzumab group, there were no significant differences in baseline lesion number ( p = 0.568) nor brain parenchymal fraction ( p = 0.187) between those who relapsed within 4 years ( n = 4) and those who did not ( n = 15). However, the baseline gradient was significantly different ( p = 0.020). Conclusion: Untreated, abnormal periventricular gradients worsen with time, but appear reversible with peripheral immunotherapy. Baseline gradients – but not lesion loads or brain volumes – may predict on-treatment relapses. Larger confirmatory studies are required.

Magnetisation transfer ratio abnormalities in primary and secondary progressive multiple sclerosis

Background: In relapse-onset multiple sclerosis (MS), tissue abnormality – as assessed with magnetisation transfer ratio (MTR) imaging – is greater in the outer cortical and inner periventricular layers. The cause of this remains unknown but meningeal inflammation has been implicated, particularly lymphoid follicles, which are seen in secondary progressive (SP) but not primary progressive (PP) MS. Cortical and periventricular MTR gradients might, therefore, differ in PPMS and SPMS if these follicles are responsible. Objective: We assessed cortical and periventricular MTR gradients in PPMS, and compared gradients between people with PPMS and SPMS. Methods: Using an optimised processing pipeline, periventricular normal-appearing white matter and cortical grey-matter MTR gradients were compared between 51 healthy controls and 63 people with progressive MS (28 PPMS, 35 SPMS). Results: The periventricular gradient was significantly shallower in healthy controls (0.122 percentage units (pu)/band) compared to PPMS (0.952 pu/band, p < 0.0001) and SPMS (1.360 pu/band, p < 0.0001). The cortical gradient was also significantly shallower in healthy controls (−2.860 pu/band) compared to PPMS (−3.214 pu/band, p = 0.038) and SPMS (−3.328 pu/band, p = 0.016). Conclusion: Abnormal periventricular and cortical MTR gradients occur in both PPMS and SPMS, suggesting comparable underlying pathological processes.