bluuebunny/crossref_metadata_2025_split huggingface dataset:
15.09 Inherited peripheral neuropathies: analysis of PDXK gene identifies a new treatable disorder
Authors: Chelban Viorica , Wilson Matthew P , Chardon Jodi Warman , Vandrovcova Jana , Natalia Zanetti M , Zamba-Papanicolaou Eleni , Efthymiou Stephanie , Pope Simon , Conte Maria R , Abis Giancarlo , Liu Yo-Tsen , Tribollet Eloise , Haridy Nourelhoda A , Botía Juan A , Ryten Mina , Nicolaou Paschalis , Minaidou Anna , Christodoulou Kyproula , Kernohan Kristin D , Eaton Alison , Osmond Matthew , Ito Yoko , Bourque Pierre , Jepson James EC , Bello Oscar , Bremner Fion , Cordivari Carla , Reilly Mary M , Foiani Martha , Heslegrave Amanda , Zetterberg Henrik , Heales Simon JR , Wood Nicholas W , Rothman James E , Boycott Kym M , Mills Philippa B , Clayton Peter T , Houlden Henry ,   for the Care4Rare Canada Consortium and the SYNaPS Study Group
Published: March 2023

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified.We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozygosity mapping and segregation analysis. Pathogenicity was confirmed via enzymatic assays and mass spectroscopy on recombinant protein and patient-derived fibroblasts, plasma and erythrocytes. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy. Pyridoxal kinase (PDXK) is involved in converting vitamin B6 to its active form, pyridoxal 5’-phosphate (PLP). We show that PDXK mutations lead to disease via decreased plasma PLP concentrations. Our functional studies revealed conformational rearrangement in the mutant enzyme around the kinase ATP-binding pocket with impaired PDXK ability to bind ATP and leading to reduced erythrocyte PDXK activity. We show that both the human clinical picture and biochemical profile in PDXK mutations are rescued by PLP supplementation. Patients regained their ability to walk independently. Furthermore, treatment-led normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, a biomarker of axonal breakdown.In conclusion, biallelic mutations in human PDXK are associated with a novel disorder leading to treatable primary axonal polyneuropathy and optic atrophy and identifies PLP as therapeutic target.
139 Risk of parkinson’s in idiopathic anosmia
Authors: Rees Richard N , Philpott Carl , Gane Simon , Worth Paul , Noyce Alastair J , Schrag Anette 
Published: March 2023

Smell loss (anosmia) is a common finding in people with PD, although it is also quite common in older age (Ross 2008). Population studies assessing the prodromal phase of PD have therefore included individuals with smell loss. However, the differential diagnosis of anosmia is broad, and it is likely that only a subset are linked to neurodegeneration. Some evidence suggests that people with the anosmic prodrome have a different phenotype to other forms of prodromal PD (Rees 2019).MethodsWe assessed neurologically healthy patients aged 60–80y from two specialist ENT clinics (James Paget Hospital, Norfolk; RNTNE, London). All participants had a diagnosis of idiopathic anosmia after comprehensive investigation. Participants completed online PREDICT-PD testing (www.predictpd.com) followed by an in-person assessment with standardised physical, cognitive and autonomic tests.ResultsWe recruited 28 participants (17 women) mean age 69.9y (SD 4.9y). Participants had a mean of 14.4 years of education (SD 3.1). Adjusted MoCA scores had a mean of 25.9/30 (SD 2.6). There was a range of subtle motor impairment, median MDS-UPDRS III 4.5 (IQR 1.0- 8.0, max 20) and median 3m up-&-go time 8.5s (IQR 7.8–9.6). Those with the highest risk had higher tremor scores in the MDS-UPDRSConclusionsThere is a correlation between risk of PD and cognition. There is no significant gross motor or autonomic dysfunction in these patients, but the highest risk participants had higher tremor subscores. Further recruitment will allow clear delineation of the anosmic prodrome of PD.
143 Dopamine transporter SPECT imaging: service evaluation from a tertiary neurosciences centre
Authors: Kobylecki Christopher , Harris Jonathan , Boyle Mark , Hoffmann Sandra 
Published: March 2023

BackgroundThe use of dopamine transporter SPECT imaging can improve diagnostic accuracy in the assessment of parkinsonism and tremors. In order to manage demand and ensure appropriate use, our tertiary neurosciences centre set up a policy of screening referrals by a movement disorder specialist (C.K.).ObjectiveTo audit the use of [123I]-ioflupane SPECT (DaTscanTM) imaging at Manchester Centre for Clinical Neurosciences.MethodsWe audited DaTscan referrals and subsequent results from May 2014-July 2018. The reason for rejection of referrals was documented and subsequent clinical course assessed. We recorded overall indications for imaging and the eventual results.ResultsIn total, we received 136 referrals for DaTscan, of which 34 (25%) were rejected. Of these, the subsequent course was consistent with the clinical impression in 30 patients for whom follow-up data were available. The most common indications for scans performed were differentiation of Parkinson’s disease from tremor syndromes (46%), and suspected drug induced parkinsonism (26%). Equivocal imaging results in 9% were reclassified as normal following quantification.ConclusionsScreening of referrals for DaTscan imaging in a movement disorder service is safe and cost-saving. Appropriate use of DaTscan imaging improves patient management, and equivocal results may be clarified by quantification techniques.
144 Studying corticobasal syndrome across the UK via the BNSU
Authors: Costantini Alyssa , Jabbari Edwin , Lamb Ruth , Darvell Marcia , Woodside John , Rohrer Jon , Lees Andrew , Morris Huw ,   on behalf of PROSPECT-UK & European CBS consortia
Published: March 2023

BackgroundThere are a number of different causes of corticobasal syndrome (CBS) and we are recruiting CBS patients across the UK to the PROSPECT-UK study.ObjectiveTo define patients with CBS and to define features that are helpful in determining the underlying pathological diagnosis.MethodsThe RaDAR platform enables the recruitment of patients with CBS. Eligible patients are anonymously invited to contact the study team. Following informed consent, patients can participate remotely or be seen at their local study site. A subset of these patients undergo deep phenotyping, including CSF analysis for total Tau and Abeta.ResultsWe have established a cohort of 179 patients with CBS for future therapeutic, biomarkers and clinical studies. Mean recruitment is 5/month. The ABN RaDAR scheme has identified 58 CBS patients across the UK through 2018 so far, and we are liaising with consultants to recruit these patients. Deep phenotyping is underway – in patients with CSF analysis, 47% have an Alzheimer disease–like CSF profile highlighting the phenotypic diversity in this group. We are continuing to analyse other features of CBS.ConclusionsWe are continuing to define the diverse pathological causes of CBS with a view to developing future disease modifying treatment trials.
145 Pre-motor phase in autopsy-confirmed multiple system atrophy
Authors: Vichayanrat Ekawat , Pablo-Fernandez Eduardo De , Valerio Fernanda , Mathias Christopher , Panicker Jalesh , Holton Janice , Warner Thomas , Quinn Niall , Iodice Valeria 
Published: March 2023

BackgroundNon-motor features can be presenting symptoms and often precede the motor features in patients with multiple system atrophy (MSA). However there have been no studies specifically looking at the conversion time, clinical features and survival rate in autopsy-confirmed MSA patients.MethodsMedical records of 47 autopsy-confirmed MSA cases at the Queen Square Brain Bank who underwent clinical examination and cardiovascular autonomic testing at the National Hospital for Neurology were reviewed.Results15/47 (32%, M:F/9:6) MSA patients had non-motor autonomic features as an initial presentation before developing motor symptoms. Mean pre-motor phase duration was 3 (range 1–6) years. Among these 15 patients, the most common pre-motor features (87%) were genitourinary (erectile dysfunction in 7, bladder dysfunction in 6 patients); pre-motor symptomatic orthostatic hypotension (OH) and REM sleep behavioural disorder (RBD) occurred in one patient each. 5/15 patients developed cardiovascular autonomic failure and were initially diagnosed with pure autonomic failure (PAF). There was no difference in age of onset between patients presenting with motor and pre-motor autonomic features (p=0.67) or between different pre-motor presenting features and disease duration (p>0.05).ConclusionsPre-motor autonomic features, including genitourinary, cardiovascular autonomic failure and RBD, are common presenting symptoms in MSA, accounting for almost one-third of patients. These features can predate motor symptoms by up to 6 years, or longer.
149 Optical coherence tomography in an irishSPG7cohort
Authors: Bogdanova-Mihaylova Petya , Chen Hongying , Plapp Helena , Murphy Sinéad M , Walsh Richard A 
Published: March 2023

Reduction of retinal nerve fibre layer (RNFL) thickness has been reported in neurodegenerative conditions, including inherited ataxias and hereditary spastic paraparesis. Mutations inSPG7are increasingly identified as a common cause of spastic ataxia.Spectral domain optical coherence tomography (OCT) was performed in 25 individuals (six females) with genetically confirmedSPG7-related spastic ataxia to quantify peripapillary RNFL thickness. Standardized examination included age of onset, mean: 40 years (range 12–61); disease duration, mean: 19.6 years (range 6–42 years) and disease severity as quantified with Scale for the Assessment and Rating of Ataxia (SARA), mean: 10.2/40 (range 3–29).Abnormal RNFL thickness in comparison to controls was detected in 12/22 patients. 3/12 patients had disease duration of less than 10 years and demonstrated predominantly temporal inferior RNFL loss. There was no significant correlation between global RNFL thickness with disease severity (R=-0.13, p=0.75) or disease duration (R=-0.31, p=0.41).RNFL abnormalities in patients with spastic paraparesis/ataxia may be suggestive ofSPG7-associated disease. OCT, non-invasive and quick, should be considered part of the neurological assessment, especially in patients with late-onset spastic ataxias. Further longitudinal studies are needed to determine whether RNFL thickness could be used as a potential biomarker for disease progression in theSPG7cohort.
151 Improving diagnosis and care in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)
Authors: Swallow Diane , Grosset Donald , Counsell Carl 
Published: March 2023

BackgroundMisdiagnosis and delayed diagnosis are common in PSP/CBD. After diagnosis there is little evidence on multidisciplinary care access or on prognosis other than survival.Aims(1) Describe and improve diagnostic pathways; (2) Validate and develop diagnostic tools; (3) Evaluate care quality from diagnosis to end-of-life; (4) Evaluate patient and carer prognosis; (5) Evaluate activity limitations as measures of disease progression and outcomes for clinical trials.MethodsIndividuals with PSP/CBD are recruited nationally across Scotland. Patients consent to medical record access, data linkage, clinical examination and questionnaires covering multiple domains, postal follow-up and MRI. Each PSP/CBD patient nominates a carer to return questionnaires about their health, carer burden and proxy assessments of their relative’s capabilities. PD controls undergo motor/cognitive examination and MRI.Results73 PSP/CBD patients, 63 carers and 26 age-sex matched PD controls have been recruited to date. 69(94.5%) PSP/CBD cases have consented to longitudinal clinical assessment, medical record review and data linkage, and 4(5.5%) to medical record/data linkage only. 56(76.7%) have consented to longitudinal MRI.Anticipated outcomes: Understanding the causes of delayed diagnosis and the assessment of new diagnostic tools will facilitate improved diagnosis. A better understanding of patient and carer prognosis will improve care planning and provision.
153 The PHQ-9 as a tool to measure depression in people with multiple sclerosis
Authors: Quigley Suzanne , Beswick Emily , Macdonald Pamela , Connick Peter 
Published: March 2023

BackgroundDepression has a point prevalence of 25% and lifetime prevalence of 50% in people with MS (pwMS). Due to its convenience, the PHQ9 may be a useful tool in clinical practice for screening and monitoring of depression in pwMSObjectivesTo evaluate the internal and external reliability of the PHQ-9 measure of depressive symptoms in people with MS. Secondary objectives are; to evaluate the validity of the PHQ-9 as a measure of depressive symptoms in people with MS and to evaluate the acceptability of the PHQ-9 to people with MSDesign: A cross section validation studySubjects: People with Multiple SclerosisMethodsPeople with MS were recruited from the Rowling Care registry at the Anne Rowling Regenerative Neurology Clinic. Participants complete three questionnaires during a 4 week period using online questionnaires. Statistical analysis will be performed at the end of the study using R StudioResultsThe study is ongoing and now in the follow up phase. Provisional results are based on 92 completed participant datasets- Internal reliability of the PHQ-9 using Cronbach’s Alpha was 0.88. External reliability of the PHQ-9 using intraclass coefficient was 0.72.ConclusionsFinal conclusions are pending due to ongoing data collection.
158 CSF T-cell counts in multiple sclerosis diagnosis and prognosis
Authors: Hrastelj James , Willis Mark , Bishop Mark , Loveless Sam , Tallantyre Emma , Robertson Neil 
Published: March 2023

BackgroundIdentifying diagnostic and prognostic biomarkers in multiple sclerosis (MS) remains challenging. Cerebrospinal fluid (CSF) is a potentially valuable source.AimTest association between CSF cell counts and (i) neuroinflammatory diagnosis, (ii) early MS disease activity.MethodsCD4+/CD8+ T-cells were counted using flow cytometry in CSF collected from 162 patients. Clinical data were collected for 12–52 months. Cell counts were tested for association with: 1) diagnostic group: MS (n=63), clinically isolated syndrome (CIS, n=11), other inflammatory disorders (n=8) and non-inflammatory disorders (NID, n=75)); 2) time to next relapse/treatment commencement; 3) MS initial course. Area under receiver operator characteristic curve (AUC) was calculated for diagnostic utility.ResultsCSF CD4+ and CD8+ counts were higher in MS vs CIS (e.g. CD4+: p=0.0063, AUC=0.76) and NID (e.g. CD4+: p=1.4×10–6, AUC=0.74). NHS laboratory CSF white cell counts (WCC) were also higher in MS vs CIS (p=0.049, AUC=0.68) and NID (p=8.9×10–10, AUC=0.73). In logistic regression models of MS vs CIS in OCB negative patients, NHS WCC explained the greatest proportion of the variance (16.5%, p=0.03, AUC=0.70), but the optimal model also included CD4+ and CD8+ counts. Cell counts did not predict initial course or clinical outcomes.ConclusionsCSF cell counts could aid diagnosis of MS. CSF cell counts alone did not predict early MS disease activity in this size cohort, but prognostic utility in combination with other biomarkers should be tested in a larger cohort.
160 Ten-year clinical outcomes post treatment with mitoxantrone for relapsing remitting MS
Authors: Foo Eng Chuan , Russell Melanie , Lily Oliver , Ford Helen 
Published: March 2023

Mitoxantrone has been used as induction or escalation treatment in highly-active relapsing-remitting multiple sclerosis (RRMS). Whilst effective, its use is limited by adverse events (AE).ObjectiveTo report the clinical effectiveness and AE profile following mitoxantrone in a patient cohort with RRMS over a 10-year follow-up period.MethodsThis retrospective study included all patients treated with mitoxantrone in the Leeds MS service between 2003 and 2015. We measured expanded disability status scale (EDSS) scores annually and recorded AEs and secondary progression (SPMS).ResultsForty-two patients (25 female, 17 male) were reviewed. Twenty-three (55%) received disease-modifying therapy (DMT) pre-mitoxantrone (17 interferon beta-1a, 4 glatiramer acetate, 2 natalizumab). Nineteen (45%) received further DMT post-mitoxantrone (1 interferon beta-1a, 9 glatiramer acetate, 5 natalizumab, 2 fingolimod, 2 dimethyl fumarate). Median pre-mitoxantrone EDSS score was 6.0 (95%CI 5–6). Median EDSS score at year 10 was 6.5 (95%CI 5–7). Nine (21%) developed SPMS. Commonest AE was nausea, n=6 (14%). Four (10%) developed serious AEs (1 arrhythmia, 1 left ventricular impairment, 1 pancytopaenia, 1 acute myeloid leukaemia). All serious AEs resolved and AML remains in remission for over 6 years.ConclusionMitoxantrone therapy is effective and relatively low risk with evidence of long-term benefits in RRMS patients.
15.33 Phenotype-genotype characterisation of ‘long survivors’ with motor neurone disease in Scotland
Authors: Leighton Danielle , Newton Judith , Parry David , Colville Shuna , Swingler Robert , Porteous Mary , Aitman Tim , Gorrie George , Chandran Siddharthan , Pal Suvankar 
Published: March 2023

The Clinical Audit Research and Evaluation of Motor Neurone Disease (CARE-MND) platform has collected information from people with MND in Scotland since 1989. In a recent analysis, upper range of survival from diagnosis was 25.8 years.We investigated phenotypes and genotypes of a ‘long-surviving’ cohort (>8 years from diagnosis). 14 phenotypic variables were analysed, and compared with unselected incident patients. DNA samples underwent whole genome sequencing and screening for C9orf72 expansions.60 long survivors were identified. 46 were alive at censorship, giving a Scottish prevalence of 11.0%. Long survivors were younger than incident patients (p<0.0001) and tended to have lower limb-onset disease (p=0.003). Disease classification differed (p<0.0001); 41.7% had primary lateral sclerosis (PLS). 7/34 (20.6%) had pathogenic/likely-pathogenic mutations. Four had SOD1 mutations; three the Scottish p.I114T founder mutation. Remaining patients had variants in FUS, ALS2 and SPG11. The individual with the SPG11 variant also had a variant of uncertain significance in the same gene.Long survivors in the Scottish MND population are younger, and have increased prevalence of PLS and lower limb-onset disease. SOD1 p.I114T variant can result in long survival. Compound heterozygosity in SPG11 may be associated with MND. Diagnostic genotyping should be considered in long duration of disease.
175 A model for participant engagement in research: the MS register
Authors: Middleton R , Allen-Philbey K , Schmierer K , Espasandin M , Roberts C , Nicholas R , Rodgers J , Lockhart-Jones H , Tuite-Dalton K , Ford DV 
Published: March 2023

ObjectivesIncrease people with MS (PwMS) engagement with research and provide increased utility to PwMS/Clinicians.BackgroundThe UK MS Register (UKMSR) was established by the MS Society to collect research and service provision data. We have now collected 8 years of Patient Reported Outcome (PRO) data from PwMS, with more than 300,000 responses, thus far with little feedback given to participants.MethodsWe report our first experience providing feedback to PwMS, Patient Public Involvement (PPI) was utilised to better design data collection and feedback instruments. Gathered responses from UKMSR users by email/phone. Focus groups with clinicians and PwMS at Barts Health NHS Trust.OutputComprehensive feedback should be accessible for all that opt-in.ResultsThe website was re-designed to graph core instruments and provide a comprehensive ‘feedback report’ for screen/print. All participants were contacted, 5596 logged-in. 4819 existing, 773 were new users. 1291 declined feedback.DiscussionAllowing feedback clearly addresses unmet needs. The increased completions of questionnaires after re-launch suggests PwMS are more engaged with research. We will carry out further research in exploring PwMS satisfaction with the new format and on the volume and depth of data.ConclusionAllowing participants to review their own detailed feedback to questionnaires facilitates increased engagement with research.
179 Early real-world experience of ocrelizumab in MS
Authors: Harding Katharine , Ingram Gillian , Horton Emma , Owen Helen , Joseph Fady , Pearson Owen 
Published: March 2023

BackgroundOcrelizumab was recently licensed for use in relapsing-remitting multiple sclerosis (MS). We present our clinical experience of ocrelizumab treatment for MS in two specialist centres in south Wales.MethodsAll patients with MS treated with ocrelizumab in Newport and Swansea between 01/08/2018 and 31/12/2018 were included. Sex ratio, age at MS onset and baseline EDSS score were calculated. Data was collated on indication for treatment and adverse effects, and data on previous DMT sequencing will be discussed.ResultsEighty-one patients (82% female) were treated in total. Mean age at onset was 32.4 years, and mean age at ocrelizumab treatment was 42.8 years. Baseline EDSS was <4.0 in 45 (55%), 4.0–6.0 in 24 (30%), and 6.0–6.5 in 12 (15%). The commonest indication was first-line treatment for active disease (n=26, 32%), followed by side effects from other disease-modifying treatment (n=20, 25%), and high JCV titre on natalizumab (n=15, 19%). Sixty-two patients (77%) had no adverse effects. Eleven patients (14%) had infections. Three patients (4%) had infusion reactions. One patient had an allergic reaction to ocrelizumab and discontinued treatment. There were no cases of PML.DiscussionOcrelizumab has been safe and well-tolerated in our cohort. Our study illustrates the value of real-world clinical data in MS.
181 Multiple Sclerosis associated with Psoriasis – is alemtuzumab the drug of choice?
Authors: Karthikeayan Venkatraman , Whittam Daniel , Copeland Yvonne , Huda Saif , Jacob Anu 
Published: March 2023

IntroductionTreatment of relapsing remitting (RRMS) may become challenging in the presence of other autoimmune disorders,. The risk of exacerbating coexisting systemic autoimmune illnesses often restricts the choice of DMT, particularly monoclonal antibodies. Psoraisis and MS are both relatively common conditions and may co-exist posing such a problemCase 1: 39 year old woman with poorly controlled psoriasis on methotrexate was diagnosed with highly active RRMS. Alemtuzumab led to rapid (within 5 days) and sustained (x months) remission of both MS and Psoriasis. Methotrexate was stopped prior to alemtuzumab.Case 2: A 34 year old man with severe chronic plaque psoriasis was diagnosed with highly active RRMS. Alemtuzumab led to a dramatic remission within days of his psoriatic skin lesions and MS. However after 3 months psoriasis recurred.ConclusionThe remarkable response of psoriasis in these cases may be reassuring to clinicians wishing to use alemtuzumab in such situations. Though the underlying biology of the response in psoriasis is not well understood, it is primarily mediated by T Cells which Alemtuzumab effectively depletes.