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BackgroundSporadic Parkinson’s disease (sPD) is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms causing sPD will be crucial to develop future “Precision Medicine” approaches. 31P-MRS is a non-invasive tool that can quantify key bionenergetic metabolites in individual patients.ObjectiveTo determine whether 31P-MRS can identify mitochondrial dysfunction in the midbrain/sub- stantia nigra of individual PD patients and correlates with trial-relevant clinical aspects of PD.Methods31P-MRS spectra were obtained from 35 sPD patients and 25 healthy, age-matched controls. Spectra were analysed using the jMRUI software package and AMARES spectral fitting algorithm. Clinical assessment included widely utilised clinical rating scales, genetic analysis and the calculation of predicted risk of rapid disease progression.ResultsThere was a significantly broader variance in 31P-MRS midbrain ATP with 1/3 of all PD patients having ATP levels > 2 standard deviations outside the mean control values (p=0.0030). Higher midbrain phosphocreatine was associated with greater risk of rapid disease progression (p= 0.0384).Conclusions31P-MRS may help to identify a subgroup of sPD with significant mitochondrial dysfunction or at higher risk of more rapid progression and facilitate stratification for future precision medicine neu- roprotective trials. Longitudinal studies are required to characterise if changes 31P-MRS measures mirror clinical progression.

BackgroundThere is strong evidence of mitochondrial dysfunction in both familial and sporadic Parkinson’s disease (PD). A biomarker reliably identifying mitochondrial dysfunction would be particularly important for future stratified/personalized medicine trials in Parkinson’s disease. A previous comparison of serum biomarkers in mitochondrial disease established that serum growth differentiation factor 15 (GDF-15) outperforms fibroblast growth factor-21 (FGF-21) and distinguishes patients with mitochondrial diseases from those without them.ObjectiveTo systematically assess GDF-15, FGF-21 and mitochondrial DNA copy number (mtDNA) levels in the serum of patients with sporadic PD and controls to determine their utility as a suitable mitochondrial biomarker panel for PD.Methods120 patients with PD and 102 age-matched controls were recruited from a single centre. GDF-15, FGF-21 and mtDNA copy number were quantified using previously established assays.ResultsFGF-21 concentrations did not significantly differ between groups. GDF-15 serum levels were significantly raised in late onset PD compared to controls and early onset PD. There was no difference in mtDNA between groups. None of the biomarkers tested showed a significant association with disease following multivariate logistic regression analysis.ConclusionSerum FGF-21, GDF-15 and blood mtDNA could not accurately differentiate between PD and controls when assessed as candidate biomarkers.

The Acute neurology unit (ANU), located at the Royal Hallamshire Hospital, Sheffield is a regional centre for a population of approximately 1.5 million. We are unusual, as our neurologists manage both hyperacute stroke and hyperacute neurology. HASU is located within our ANU. We had 4026 neurology ward admissions, 3265 emergency cases and 761 elective cases last year. We receive acute admissions from Trust A and E, direct admissions from general practitioners and urgent transfers from DGHs.We provide 24 hour stroke thrombolysis and a weekday working hours thrombectomy service. Overnight thrombolysis is supervised through a regional ‘Telemedicine’ system. A 2 week survey in July 2017 showed that only 59% patients, who were referred with suspected stroke, had stroke/TIA. Neurological conditions, such as migraine, seizure, syncope, acute vestibulopathy, Bell’s palsy and medically unexplained symptoms were common ‘stroke mimics’. 46% of patients with ‘stroke mimic’ were discharged on the day of admission. Average length of stay was 3 days. A separate survey of acute neurology referrals showed that 58% of patients did not require admission and were managed through an ambulatory care pathway. Patient satisfaction regarding their rapid assessment and diagnosis was high. Co-location of ANU and HASU allows rapid and effective management of ‘stroke mimics’.

ObjectiveTo determine if glucocerebrosidase 1 deficiency is a susceptibility factor to 1-methyl-4-phenylpyridinium (MPP+) toxicity using a zebrafish model.Background and hypothesisHeterozygous mutations in the glucocerebrosidase gene (GBA1) are a strong genetic risk factor for Parkinson's disease (PD). Genetic risk factors may increase susceptibility to exogenous neurotoxins. We hypothesized GBA1 haploinsufficiency may increase susceptibility to the classical PD neurotoxin MPTP.MethodsA stable gba1+/− zebrafish line was in-crossed to generate embryos of all genotypes. At 2 days post fertilization (dpf), 100 dechorionated embryos (and 100 controls) were separated into 6 well plates, and exposed to 3 mM MPP+. At 3dpf embryos were fixed in 4% paraformaldehyde. Whole mount in-situ hybridisation was performed using a tyrosine hydroxylase (TH) probe. Embryos were genotyped for gba1 by PCR. TH positive neurons were counted in 10 embryos of each genotype under 20x microscopy.ResultsMPP+ embryos exhibited approximately 25% reduction in TH neurons compared to controls with no differences between genotypes.ConclusionMPP+ exposure results in a loss of TH positive neurons. GBA1 deficiency does not potentiate this. We provide “proof of principle” data for the usefulness of PD mutant zebrafish strains to test possible interactions between PD genetic risk factors and relevant toxins.

Introduction Plasmapheresis has been shown in a randomised clinical trial (RCT) to be effective in treating corticosteroid-refractory central nervous system (CNS) inflammatory diseases. Data from our centre was compared with the published trial. Methods A retrospective case note review of patients with CNS inflammatory diseases receiving plasmapheresis was performed. Power and gait scores from Weinshenker et al . (1999) and decimal visual acuity were recorded. Results Data from 25 patients (optic neuritis=7, multiple sclerosis=12, neuromyelitis optica=4, acute disseminated encephalomyelitis=1, transverse myelitis=1) was reviewed. For the optic neuritis patients the mean visual acuity of the worse affected eye improved from 0.061 to 0.264 (p=0.157), equivalent to a change from approximately 6/100 to 6/24. For patients with a motor deficit, the mean power score improved from 5.78 to 4.78 (p=0.0218) and the mean gait score improved from 7.78 to 6.78 (p=0.0218). The mean motor improvement was from being wheelchair dependent to being able to walk a few steps with bilateral assistance. No benefit was observed if plasmapheresis commenced more than 82.7 days after onset of symptoms. No serious adverse events occurred. Conclusions Benefits in line with the results of the RCT have been detected supporting the use of plasmapheresis in these diseases.