ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK.

PURPOSE: Genetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of these findings. The genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis (ADAMS) project aims to gather genetic and phenotypic data on a large cohort of ancestrally-diverse individuals with MS living in the UK. PARTICIPANTS: Adults with self-reported MS from diverse ancestral backgrounds. Recruitment is via clinical sites, online (https://app.mantal.co.uk/adams) or the UK MS Register. We are collecting demographic and phenotypic data using a baseline questionnaire and subsequent healthcare record linkage. We are collecting DNA from participants using saliva kits (Oragene-600) and genotyping using the Illumina Global Screening Array V.3. FINDINGS TO DATE: As of 3 January 2023, we have recruited 682 participants (n=446 online, n=55 via sites, n=181 via the UK MS Register). Of this initial cohort, 71.2% of participants are female, with a median age of 44.9 years at recruitment. Over 60% of the cohort are non-white British, with 23.5% identifying as Asian or Asian British, 16.2% as Black, African, Caribbean or Black British and 20.9% identifying as having mixed or other backgrounds. The median age at first symptom is 28 years, and median age at diagnosis is 32 years. 76.8% have relapsing-remitting MS, and 13.5% have secondary progressive MS. FUTURE PLANS: Recruitment will continue over the next 10 years. Genotyping and genetic data quality control are ongoing. Within the next 3 years, we aim to perform initial genetic analyses of susceptibility and severity with a view to replicating the findings from European-ancestry studies. In the long term, genetic data will be combined with other datasets to further cross-ancestry genetic discoveries.

Osmotic demyelination syndrome despite appropriate gradual correction of moderate hyponatraemia.

Osmotic demyelination syndrome characteristically follows rapid correction of hyponatraemia. We present a young woman with a subacute progressive brainstem syndrome and diffuse pontine signal abnormality on MR imaging, diagnosed as osmotic demyelination syndrome. The case posed a diagnostic challenge due to comorbid Behçet's disease and the absence of significant fluctuation in her serum sodium concentration. Osmotic demyelination syndrome is not limited to patients with rapidly corrected hyponatraemia, especially when there are other risk factors. These factors, all present in this patient, include hypokalaemia, hypophosphataemia, malnutrition, harmful alcohol use and liver dysfunction.

Development of Autoimmune Thyroid Disease in Multiple Sclerosis Patients Post-Alemtuzumab Improves Treatment Response.

CONTEXT: Alemtuzumab is an anti-CD52 monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). Between 20% and 40% of alemtuzumab-treated MS patients develop autoimmune thyroid disease (AITD) as a side effect. OBJECTIVE: The objective of this work is to determine whether MS disease progression following alemtuzumab treatment differs in patients who develop AITD compared to those who do not. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of 126 patients with relapsing-remitting MS receiving alemtuzumab from 2012 to 2017 was conducted at a tertiary referral center. MAIN OUTCOME MEASURES: Thyroid status, new relapses, Expanded Disability Status Scale (EDSS) score change, and disability progression following alemtuzumab were evaluated. RESULTS: Twenty-six percent (33 out of 126, 25 female, 8 male) of alemtuzumab-treated patients developed AITD, 55% of which was Graves disease. EDSS score following alemtuzumab was reduced in patients who developed AITD compared to those who did not (median [interquartile range]; AITD: -0.25 [-1 to 0.5] vs non-AITD: 0 [1-0]. P = .007]. Multivariable regression analysis confirmed that the development of AITD was independently associated with EDSS score improvement (P = .011). Moreover, AITD patients had higher relapse-free survival following alemtuzumab (P = .023). There was no difference in the number of new focal T2 lesions and contrast-enhancing magnetic resonance imaging lesions developed following alemtuzumab between the 2 groups. CONCLUSION: Graves disease was the most common form of AITD developed by MS patients following alemtuzumab. This study suggests that MS patients who develop AITD may have an improved response to alemtuzumab, as measured by reduced disability and lower relapse rate.

Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [18F]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter.

PURPOSE: Measurements of non-displaceable binding (VND) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure VND for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (VT) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify VND for two TSPO radiotracers, [18F]GE-180 and [11C]PBR28, in cohorts of people with multiple sclerosis (MS). Additionally, we compared plots of subjects carrying high (HAB) or mixed binding (MAB) affinity polymorphisms of TSPO to estimate VND without receptor blockade. PROCEDURES: Twelve people with MS underwent baseline MRI and 90-min dynamic [18F]GE-180 PET or [11C]PBR28 PET (n = 6; three HAB, three MAB each). Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model. VND was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173) and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). RESULTS: Whole brain VT (mean ± standard deviation) was 0.29 ± 0.17 ml/cm3 for [18F]GE-180 and 5.01 ± 1.88 ml/cm3 for [11C]PBR28. Using the occupancy and polymorphism plots respectively, VND for [18F]GE-180 was 0.11 ml/cm3 (95 % CI = 0.02, 0.16) and 0.20 ml/cm3 (0.16, 0.34), accounting for, on average, 55 % of VT in the whole brain. For [11C]PBR28, these values were 3.81 ml/cm3 (3.02, 4.21) and 3.49 ml/cm3 (1.38, 4.27), accounting for 67 % of average whole brain VT. CONCLUSIONS: Although VT for [18F]GE-180 is low, indicating low brain penetration, half the signal shown by MS subjects reflected specific TSPO binding. VT for [11C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimating TSPO levels.

Schizophrenia does not adversely affect the treatment of women with breast cancer: a cohort study.

BACKGROUND: Data on the natural course of patients with breast cancer and schizophrenia are limited. Although there have been studies in assessing the incidence of breast cancer in the setting of schizophrenia, there is very little information concerning the clinical profile of these women. METHODS: We analyzed the data from our electronic notes system by searching for the terms 'schizophrenia' or 'schizophrenic' and 'breast cancer' or 'tumour' between 1993 and 2009. Information was collected on demographics, clinico-pathologic disease variables, treatment including anti-emetic use, chemotherapy delivery and outcomes. RESULTS: From 90,676 patients screened, we identified 37 individuals who had breast cancer and a pre-existing underlying diagnosis of schizophrenia. Of these, 30 (81%) presented with early breast cancer and 7 (19%) presented with metastatic disease. Node positivity was observed in 14 individuals (38%). The average interval between diagnosis of schizophrenia and breast cancer was more than 20 years in the majority of the patients. Treatment outcomes, trial involvement, compliance and ability to provide informed consent were similar to our previously published cohort data. CONCLUSIONS: Schizophrenia does not affect treatment delivery or outcomes in women with breast cancer. The presence of schizophrenia should not be a limiting factor for entry into clinical trials. Breast cancer patients with this illness should be offered standard treatment without discrimination, including entry into clinical trials.