Quantitative magnetic resonance imaging (qMRI) has recently shown its benefit in a longitudinal study of lower limb muscles in dysferlinopathy. This study has demonstrated the differential muscle involvement by measuring muscle fat fraction (FF) and significant yearly increases in FF. Additionally, muscle water T2, reflecting the disease activity (i.e. inflammation, edema), was found to be persistently elevated. Other anatomical regions are known to be affected later in the disease progression of dysferlinopathy, so upper limb muscles were investigated in a follow-up natural history study, Jain COS2. Here, we report preliminary baseline results. The qMRI data were acquired on two 3-tesla clinical systems at two centers in Europe between July 2019 and March 2022, in patients (n=27) and controls (n=4). qMRI acquisitions included fat-water imaging and water T2 mapping at the level of the arm (deltoid, triceps, biceps brachialis) and forearm (extensor, flexor). Student's t-tests were performed (P<0.05). Overall, patients (13 female, 14 male, 61% ambulant) were 41±12 years old and had symptoms for 17±9 years. No differences in demographic data for age, sex and years since symptoms existed between sites (P>0.132) although patients were slightly younger in site 1. Whereas in site 2, albeit one patient was assigned to limb-girdle muscular dystrophy type R2 (LGMD R2), site 2 patients were assigned to LGMD R2 or Miyoshi myopathy/other phenotypes in a 50/50 ratio (P=0.004). For all investigated muscles, FF values were significantly higher in patients than in controls (P<0.001). Although FF values were lower in patients at site 1, differences with site 2 were not significant (P<0.125). The lowest FF values were observed in the extensor muscle (site 1: 12.0±6.0%, site 2: 12.1±6.0%, P=0.463) while the highest FF was seen in deltoid muscle (site 1: 27.4±19.0%, site 2: 32.1±21.4%, P=0.278), confirming the predominant proximo-distal muscle involvement in dysferlinopathy. Muscle involvement showed a high inter-individual patient variability, at least for the arm muscles. Water T2 values were increased as compared to controls (90% percentile in controls = 36.5ms) in triceps muscle in both sites (site 1: 39.3±3.0 ms, site 2: 37.2±4.9 ms), which is in line with the finding of elevated water T2 values in lower limb in earlier work. These baseline qMRI results give a quantitative view on the disease progression and activity in the upper limb muscles of dysferlinopathy patients.

The Jain Foundation COS of dysferlinopathy is an international study in genetically confirmed dysferlinopathy patients, with the aim to identify relevant outcome measures to facilitate trial readiness. Due to its wide range of clinical phenotypes and rates of disease progression, an objective marker to quantify disease progression would be ideal. We assessed the application of quantitative magnetic resonance imaging (MRI) as a prognostic tool for these patients. Our aim is to establish whether there is a correlation between fat fraction (FF) in thigh and/or lower leg muscles and clinical outcome assessments (COA) when comparing baseline (BL) values and changes from BL to year 1 (Y1) and to year 3 (Y3). We selected 84 patients from COS1 who had a Dixon MRI of the lower limbs (LL) and at least one of the following COA: time to rise from floor (RFF), time to climb / descend 4 steps (4SC/4SD), time up and go (TUG), time to walk 10m (10MWT), 6 min walk test (6MWT) and North Star Assessment for limb girdle type muscular dystrophy (NSAD) score. Spearman correlation (rs) was performed using SPSS statistics, p value 0.05. We found a significant correlation at BL between LL FF values and all COA, with the highest rs between thigh FF and NSAD (-.675) and 6MWT (-.665). We didn't find any correlations between changes in FF between BL and Y1 and changes in COA during that same period, but we did observe a significant correlation with changes in TUG (.445) and 4SC (.41) between BL and Y3. We observed a significant correlation between changes in thigh FF between BL and Y3 and changes in TUG (.706), RFF (.607), 4SC (.545) and NSAD[HR1] (-.374). No correlations were found when analysing changes in lower legs FF and COA. Our results show that changes in FF of the thigh muscles over one year could predict functional changes at a later stage, in a three-year period, suggesting that MRI could be used to identify dysferlinopathy patients at risk of more severe disease progression in routine clinical care. The Jain Foundation COS of dysferlinopathy is an international study in genetically confirmed dysferlinopathy patients, with the aim to identify relevant outcome measures to facilitate trial readiness. Due to its wide range of clinical phenotypes and rates of disease progression, an objective marker to quantify disease progression would be ideal. We assessed the application of quantitative magnetic resonance imaging (MRI) as a prognostic tool for these patients. Our aim is to establish whether there is a correlation between fat fraction (FF) in thigh and/or lower leg muscles and clinical outcome assessments (COA) when comparing baseline (BL) values and changes from BL to year 1 (Y1) and to year 3 (Y3). We selected 84 patients from COS1 who had a Dixon MRI of the lower limbs (LL) and at least one of the following COA: time to rise from floor (RFF), time to climb / descend 4 steps (4SC/4SD), time up and go (TUG), time to walk 10m (10MWT), 6 min walk test (6MWT) and North Star Assessment for limb girdle type muscular dystrophy (NSAD) score. Spearman correlation (rs) was performed using SPSS statistics, p value 0.05. We found a significant correlation at BL between LL FF values and all COA, with the highest rs between thigh FF and NSAD (-.675) and 6MWT (-.665). We didn't find any correlations between changes in FF between BL and Y1 and changes in COA during that same period, but we did observe a significant correlation with changes in TUG (.445) and 4SC (.41) between BL and Y3. We observed a significant correlation between changes in thigh FF between BL and Y3 and changes in TUG (.706), RFF (.607), 4SC (.545) and NSAD[HR1] (-.374). No correlations were found when analysing changes in lower legs FF and COA. Our results show that changes in FF of the thigh muscles over one year could predict functional changes at a later stage, in a three-year period, suggesting that MRI could be used to identify dysferlinopathy patients at risk of more severe disease progression in routine clinical care.

Background Lithium treatment is associated with an increase in magnetic resonance imaging derived measures of white matter integrity, but the relationship between the spatial distribution of brain lithium and white matter integrity is unknown. Methods Euthymic patients with bipolar disorder receiving lithium treatment (n=12) and those on other medications but naïve to lithium (n=17) underwent diffusion imaging alongside matched healthy controls (n=16). Generalised fractional anisotropy (gFA) within white matter was compared between groups using a standard space white matter atlas. Lithium-treated patients also underwent novel multinuclear 3D lithium magnetic resonance imaging (7Li-MRI) to determine relative lithium concentration across the brain. The relationship between 7Li-MRI signal intensity and gFA was investigated at the resolution of the 7Li-MRI sequence in native space. Results The lithium-treated bipolar disorder and healthy control groups had higher mean gFA in white matter than the bipolar disorder group treated with other medications but naïve to lithium (t = 2.5, p < 0.05; t = 2.7, p < 0.03, respectively). No differences in gFA were found between patients taking lithium and healthy controls (t = 0.02, p = 1). These effects were seen consistently across most regions in the white matter atlas. In the lithium-treated group, a significant effect of the 7Li-MRI signal in predicting the gFA ( p < 0.01) was identified in voxels containing over 50% white matter. Conclusions Lithium treatment of bipolar disorder is associated with higher gFA throughout brain white matter, and the spatial distribution of lithium is also positively associated with white matter gFA.

The Jain Clinical Outcome Study of Dysferlinopathy (COS) is an international study that recruited 197 patients with genetically confirmed dysferlinopathy. COS aims to identify the most relevant outcome measures for this heterogeneous degenerative disease to facilitate trial readiness. We report findings in a subset of 49 subjects at Newcastle and Paris. Lower limbs were imaged using gradient-echo 3-point Dixon with site-specific optimized echo times (Newcastle 3T Philips: E1/TE2/TE3 = 3.45/4.6/5.75 ms; Paris 3T Siemens: TE1/TE2/TE3=2.75/3.95/5.15 ms). Thigh and leg muscles were manually delineated to obtain mean Fat Fraction (FF) value per muscle per year. We examined the relationship between change in functional motor performance as measured by the North Star for Dysferlinopathy (NSAD) and weighted FF per segment (one for leg and one for thigh). We stratified the cohort at baseline using the NSAD to identify different trajectories of disease progression. Weighted FF at baseline does not predict clinical severity, with overlap between mild, moderate and severe disease. At above 60% FF, most of the subset are noted to have severe disease. Below 10% FF, most are defined clinically as mild. There is considerable overlap between severity groupings using a mean FF for weighted segments. A more detailed analysis evaluating individual muscles will be presented. After three years, a rapid clinical decline in motor ability measured by NSAD was observed in 13 subjects compared to whole COS cohort average change. Analysis of 2 and 3 year MRI data is ongoing. We will report on the further examination of the cohort 's FF change over three years and the interaction between pathology on MRI and motor performance. Progression in dysferlinopathy can be demonstrated using functional outcomes measured by Physiotherapists and quantitative MRI over three years. The relationship appears to be non-linear between muscle pathology and functional motor performance.

BACKGROUND:Proton longitudinal relaxation (T1 ) is a quantitative MRI-derived tissue parameter sensitive to myelin, macromolecular, iron and water content. There is some evidence to suggest that cortical T1 is elevated in bipolar disorder and that lithium administration reduces cortical T1 . However, T1 has not yet been quantified in separate groups containing lithium-treated patients, lithium-naïve patients, and matched healthy controls. METHODS:Euthymic patients with bipolar disorder receiving lithium (n = 18, BDL) and those on other medications but naïve to lithium (n = 20, BDC) underwent quantitative T1 mapping alongside healthy controls (n = 18, HC). T1 was compared between groups within the cortex, white matter and subcortical structures using regions of interest (ROI) derived from the Desikan-Killiany atlas. Effect sizes for each ROI were computed for BDC vs BDL groups and Bipolar Disorder vs HC groups. RESULTS:No significant differences in T1 were identified between BDL and BDC groups when corrected for multiple comparisons. Patients with bipolar disorder had significantly higher mean T1 in a range of ROIs compared to healthy controls, including bilateral motor, somatosensory and superior temporal regions, subcortical structures and white matter. CONCLUSIONS:The higher T1 values observed in the patients with bipolar disorder may reflect abnormal tissue microstructure. Whilst the precise mechanism remains unknown, these findings may have a basis in differences in myelination, macromolecular content, iron and water content between patients and controls.

Lithium is a major treatment for bipolar disorder and the likelihood of a favourable response may be determined by its distribution in the brain. Lithium can be directly detected by magnetic resonance (MR), but previous 7 Li MR spectroscopy studies have demonstrated that this is challenging compared to conventional 1 H MR imaging due to the MR properties of the lithium nucleus and its low concentration in brain tissue, as dictated by therapeutic dose. We have tested and implemented a highly efficient balanced steady-state free precession 7 Li-MRI method to address these challenges and enable MRI of brain lithium in a short duration scan. We report a 3D 7 Li-MRI acquisition with 25 mm isotropic resolution in an 8-min scan that demonstrates heterogeneity in lithium concentration within the brain in subjects with bipolar disorder. This represents the direct imaging of a pharmaceutical agent in its target organ and notably expands the repertoire of techniques available to investigate the effects of lithium in man.

Background: The Clinical Outcome Study in Dysferlinopathy is an international natural history study. 203 genetically confirmed adults have been recruited across 15 sites in 8 countries.

We report on longitudinal clinical outcome data over the first year of a 3-year natural history study of dysferlinopathy. 203 adults with dysferlinopathy have been recruited across 15 sites in 8 countries. Physiotherapy assessments are made at baseline, 6 months and one year to assess respiratory involvement (FVC sitting), muscle strength (Manual muscle testing (MMT), hand held Dyometry (HHD) and functional ability (modified North Star Ambulatory Assessment, Jebsen Test, Motor Function Measure (MFM-20). The six minute walk and timed tests (Rise from floor, 10 metre walk/run, four stair climb and descend, timed Up and Go) are also performed. Quantitative magnetic resonance imaging (MRI) is made annually with MRI based on fat/water separation (Dixon techniques) and muscle water T2 mapping (Multi-Slice Multi-Echo, MSME). 31P magnetic resonance spectroscopy (MRS) is also performed in the tibialus anterior (TA) muscle to determine metabolic changes in a subgroup of patients. The strength assessments detected statistically significant change over a year in multiple muscle groups. MMT showed significant change with shoulder abduction, elbow flexion biceps, wrist flexion, hip adduction and hip flexion. HHD also indicated significant change for elbow flexion biceps, hip adduction, elbow flexion brachioradialis, grip, pinch, knee extension, knee flexion and ankle PF knee bent. The functional tests, MFM and NSAA both highlighted statistically significant change as did stacking cans and writing on the Jebsen. All timed tests were statistically sensitive to change over a year. MRI fat fraction showed significant change over a year in both the thigh and calf muscles. In the opposite, water T2 did not change significantly. These data allow exploration of relationships between physiotherapy data and MRI with respect to how these potential outcome measures perform in the dysferlin population.

The structure and reactivity of molecular dications has been the subject of increasing attention from theoreticians and experimentalists. We consider vibrationally resolved spectra of molecular dications, with particular emphasis on the interpretation of the observed spectral lines, before reviewing in detail all known high resolution spectra of molecular dications. We give a progress report on the state of our own calculations and ion beam measurements of the molecular dications DCl2+ and NO2+.

We have obtained hyperfine-resolved infrared spectra of a (P)Q(23)(N) branch line in the u =2-1 band of the X (3)Sigma(-) state of the molecular dication (DCl2+)-Cl-35. Analysis of the hyperfine structure allows us to estimate the magnitude of the Fermi contact interaction for the chlorine nucleus; b(F)(Cl) = 167 (25) MHz.

Collinear laser-beam/ion-beam spectroscopy provides a collision-free environment in which to study atomic and molecular ions. Ion-beam spectroscopy has particular advantages over other methods: spectra are relatively simple due to mass selection; kinematics allow sub-Doppler resolution of the whole velocity distribution; and the Doppler effect can be used to tune ions into resonance with fixed frequency light sources. We consider methods by which spectra have been obtained and review important results of ion-beam spectroscopy in fields from nuclear physics to astrophysical chemistry.