ORCID Profile
0000-0002-2358-7348
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Publisher: Oxford University Press (OUP)
Date: 24-10-2023
Publisher: Springer Science and Business Media LLC
Date: 29-10-2018
DOI: 10.1007/S12035-018-1404-2
Abstract: The degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer's disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the p75 neurotrophin receptor (p75
Publisher: Frontiers Media SA
Date: 03-04-2019
Publisher: Wiley
Date: 11-01-2022
DOI: 10.1111/ENE.15237
Abstract: The aim was to evaluate urinary neopterin, a marker of pro‐inflammatory state, as a potential biomarker of disease prognosis and progression in amyotrophic lateral sclerosis (ALS) and to compare its utility to urinary neurotrophin receptor p75 extracellular domain (p75 ECD ). This was an observational study including 21 healthy controls and 46 people with ALS, 29 of whom were s led longitudinally. Neopterin and p75 ECD were measured using enzyme‐linked immunoassays. Baseline and longitudinal changes in clinical measures, neopterin and urinary p75 ECD were examined, and prognostic utility was explored by survival analysis. At baseline, urinary neopterin was higher in ALS compared to controls (181.7 ± 78.9 μmol/mol creatinine vs. 120.4 ± 60.8 μmol/mol creatinine, p = 0.002, Welch's t test) and correlated with the Revised ALS Functional Rating Scale ( r = −0.36, p = 0.01). Combining previously published urinary p75 ECD results from 22 ALS patients with a further 24 ALS patients, baseline urinary p75 ECD was also higher compared to healthy controls (6.0 ± 2.7 vs. 3.2 ± 1.0 ng/mg creatinine, p 0.0001) and correlated with the Revised ALS Functional Rating Scale ( r = −0.36, p = 0.01). Urinary neopterin and p75 ECD correlated with each other at baseline ( r = 0.38, p = 0.009). In longitudinal analysis, urinary neopterin increased on average (±SE) by 6.8 ± 1.1 µmol/mol creatinine per month ( p 0.0001) and p75 ECD by 0.19 ± 0.02 ng/mg creatinine per month ( p 0.0001) from diagnosis in 29 ALS patients. Urinary neopterin holds promise as marker of disease progression in ALS and is worthy of future evaluation for its potential to predict response to anti‐inflammatory therapies.
Publisher: Frontiers Media SA
Date: 07-07-2020
Publisher: Wiley
Date: 28-10-2019
DOI: 10.1111/NAN.12578
Abstract: Mutations in TANK binding kinase gene (TBK1) are causative in amyotrophic lateral sclerosis (ALS), however correlations between clinical features and TBK1 mutations have not been fully elucidated. We aimed to identify and compare TBK1 mutations to clinical features in a cohort of ALS patients from Northern England. TBK1 mutations were analysed in 290 ALS cases. Immunohistochemistry was performed in brain and spinal cord of one case with a novel in-frame deletion. Seven TBK1 variants were identified, including one novel in-frame deletion (p.85delIle). In silico analysis and literature suggested four variants were pathogenic, and three were variants of uncertain significance or benign. Post-mortem immunohistochemistry established an in idual with the novel in-frame deletion had classical ALS and Type B FTLD-TDP pathology, with no changes in TBK1 staining or interferon regulatory factor IRF3. TBK1 mutations were present in 1.38% of our cohort, and screening showed no clear genotype-phenotype associations compared to other genetic and sporadic ALS cases. TBK1 immunohistochemistry was consistent with previously published literature and we are the first to show no differential expression of interferon regulatory factor IRF3, a downstream effector of TBK1 in the immune pathway, in the TBK1-mutant tissue, compared to controls.
Publisher: Springer International Publishing
Date: 10-11-2021
Publisher: Public Library of Science (PLoS)
Date: 27-01-2014
Publisher: Springer Science and Business Media LLC
Date: 11-07-2017
DOI: 10.1038/S41598-017-05430-W
Abstract: To comprehensively assess whether p75 ECD in urine could be a candidate biomarker for ALS evaluation. Urine s les were collected from 101 ALS patients, 108 patients with other neurological disease (OND) and 97 healthy controls. 61 ALS patients were followed up with clinical data including ALSFRS-r every 6 to 12 months, 23 ALS patients died and 17 ALS patients lost touch during follow up period. Enzyme-linked immunoassay was employed to determine urine p75 ECD concentration. The ALSFRS-r was employed to assess the severity of ALS. The concentration of p75 ECD in ALS was significantly higher than that of OND and CTRL (p 0.001). Additionally, urine p75 ECD concentrations in ALS-definite grade patients were significantly higher than that in ALS-probable grade and ALS-possible grade patients (p 0.001). Higher urine p75 ECD concentrations were correlated with increased clinical stage (p = 0.0309) urine p75 ECD concentrations and ALSFRS-r were negatively correlated (p = 0.022) and urine p75 ECD concentration in the fast-progressing ALS group was significantly higher than that in slow-progression (p = 0.0026). Our finding indicates that urine p75 ECD concentration provides additional evidence for patients with clinically suspected ALS, and can be employed to evaluate ALS-severity.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-02-2017
DOI: 10.1212/WNL.0000000000003741
Abstract: To evaluate urinary neurotrophin receptor p75 extracellular domain (p75 ECD ) levels as disease progression and prognostic biomarkers in amyotrophic lateral sclerosis (ALS). The population in this study comprised 45 healthy controls and 54 people with ALS, 31 of whom were s led longitudinally. Urinary p75 ECD was measured using an enzyme-linked immunoassay and validation included intra-assay and inter-assay coefficients of variation, effect of circadian rhythm, and stability over time at room temperature, 4°C, and repeated freeze-thaw cycles. Longitudinal changes in urinary p75 ECD were examined by mixed model analysis, and the prognostic value of baseline p75 ECD was explored by survival analysis. Confirming our previous findings, p75 ECD was higher in patients with ALS (5.6 ± 2.2 ng/mg creatinine) compared to controls (3.6 ± 1.4 ng/mg creatinine, p 0.0001). Assay reproducibility was high, with p75 ECD showing stability across repeated freeze-thaw cycles, at room temperature and 4°C for 2 days, and no diurnal variation. Urinary p75 ECD correlated with the revised ALS Functional Rating Scale at first evaluation ( r = −0.44, p = 0.008) and across all study visits ( r = −0.36, p 0.0001). p75 ECD also increased as disease progressed at an average rate of 0.19 ng/mg creatinine per month ( p 0.0001). In multivariate prognostic analysis, bulbar onset (hazard ratio [HR] 3.0, p = 0.0035), rate of disease progression from onset to baseline (HR 4.4, p 0.0001), and baseline p75 ECD (HR 1.3, p = 0.0004) were predictors of survival. The assay for urinary p75 ECD is analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75 ECD provides prognostic information and is currently the only biological fluid–based biomarker of disease progression.
Publisher: BMJ
Date: 14-02-2021
Abstract: The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care. We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases. 21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074). Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephanie Shepheard.