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  • Real-time EEG feedback during simultaneous EEG-fMRI identifies the cortical signature of motor imagery.

    17 November 2017

    Motor imagery (MI) combined with real-time electroencephalogram (EEG) feedback is a popular approach for steering brain-computer interfaces (BCI). MI BCI has been considered promising as add-on therapy to support motor recovery after stroke. Yet whether EEG neurofeedback indeed targets specific sensorimotor activation patterns cannot be unambiguously inferred from EEG alone. We combined MI EEG neurofeedback with concurrent and continuous functional magnetic resonance imaging (fMRI) to characterize the relationship between MI EEG neurofeedback and activation in cortical sensorimotor areas. EEG signals were corrected online from interfering MRI gradient and ballistocardiogram artifacts, enabling the delivery of real-time EEG feedback. Significantly enhanced task-specific brain activity during feedback compared to no feedback blocks was present in EEG and fMRI. Moreover, the contralateral MI related decrease in EEG sensorimotor rhythm amplitude correlated inversely with fMRI activation in the contralateral sensorimotor areas, whereas a lateralized fMRI pattern did not necessarily go along with a lateralized EEG pattern. Together, the findings indicate a complex relationship between MI EEG signals and sensorimotor cortical activity, whereby both are similarly modulated by EEG neurofeedback. This finding supports the potential of MI EEG neurofeedback for motor rehabilitation and helps to better understand individual differences in MI BCI performance.

  • Genetic screening in sporadic ALS and FTD.

    22 November 2017

    The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision.

  • Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

    27 October 2017

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.

  • Influence of the blood-CSF-barrier function on S100B in neurodegenerative diseases.

    27 October 2017

    OBJECTIVES: S100B was proposed to be a CSF and blood biomarker in a number of neurological diseases. The route of S100B to the CSF and the blood in neurodegenerative diseases is unclear. To assess the impact of the physiological or impaired blood-CSF-barrier (BCSFB) function on S100B concentrations in CSF and serum, we analysed S100B in correlation of the albumin quotient. MATERIALS AND METHODS: S100Bserum and S100BCSF were quantified in samples from patients with a variety of neurological diseases using an immunoluminometric assay (Sangtec LIA-mat). Measures were analysed for a potential relation to the CSF/serum-albumin quotient (Qalb ), which indicates the BCSFB functionality. RESULTS: We reasserted increased S100B concentrations in CSF and serum of CJD patients. Elevated S100Bserum correlated with elevated S100BCSF in all diagnoses but with exceptions. Neither S100BCSF nor S100Bserum did correlate with Qalb , even when the BCSFB function was progressively impaired as demonstrated by increased Qalb . CONCLUSIONS: The lack of correlation between Qalb and S100BCSF is typically seen for proteins which are brain derived. Therefore, we propose that S100B enters the blood with the bulk flow via Pacchioni's granules and along the spinal nerve sheaths.

  • Limited role of free TDP-43 as a diagnostic tool in neurodegenerative diseases.

    17 November 2017

    TAR DNA-binding protein 43 (TDP-43) is one of the neuropathological hallmarks in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It is present in patients' blood and cerebrospinal fluid (CSF); however, the source and clinical relevance of TDP-43 measurements in body fluids is uncertain. We investigated paired CSF and serum samples, blood lymphocytes, brain urea fractions and purified exosomes from CSF for TDP-43 by one- (1D), and two-dimensional (2D) Western immunoblotting (WB) and quantitative mass spectrometry (MRM) in patients with ALS, FTLD and non-neurodegenerative diseases. By means of 2D-WB we were able to demonstrate a similar isoform pattern of TDP-43 in lymphocytes, serum and CSF in contrast to that of brain urea fractions with TDP-43 pathology. We found that the TDP-43 CSF to blood concentration ratio is about 1:200. As a possible brain specific fraction we found TDP-43 in exosome preparations from CSF by immunoblot and MRM. We conclude that TDP-43 in CSF originates mainly from blood. Measurements of TDP-43 in CSF and blood are of minor importance as a diagnostic tool, but may be important for monitoring therapy effects of TDP-43 modifying drugs.

  • Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update.

    17 November 2017

    Frontotemporal lobar degeneration (FTLD) is a spectrum of rare neurodegenerative diseases with overlapping symptoms and neuropathology. It includes the behavioral variant of frontotemporal dementia (bvFTD), the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy, and corticobasal syndrome. The diagnosis of the FTLD spectrum of diseases is based on clinical symptoms which hampers the differentiation of the diseases among each other and with other disorders that show a similar clinical appearance resulting in a high rate of misdiagnoses. This highlights the need for objective and selective measures in the diagnostic criteria and there is extensive research on neurochemical biomarkers in FTLD as one option to address this unmet clinical need. Here, we review the advances in CSF biomarker research in FTLD in the last 2 years with regard to the validation of previously suggested and identification of new biomarker candidates for the differential diagnosis of FTLD. New biomarkers for frontotemporal lobar degeneration (FTLD) are urgently needed to support differential diagnosis within the disease spectrum and with related neurodegenerative diseases such as Alzheimer disease (AD). Here, we review the advances in cerebrospinal fluid biomarker research in FTLD and provide a list of promising candidate markers.

  • Cerebrospinal fluid proteomics and protein biomarkers in frontotemporal lobar degeneration: Current status and future perspectives.

    17 November 2017

    Frontotemporal lobar degeneration (FTLD) comprises a spectrum of rare neurodegenerative diseases with an estimated prevalence of 15-22 cases per 100,000 persons including the behavioral variant of frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA), semantic dementia (SD), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The pathogenesis of the diseases is still unclear and clinical diagnosis of FTLD is hampered by overlapping symptoms within the FTLD subtypes and with other neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Intracellular protein aggregates in the brain are a major hallmark of FTLD and implicate alterations in protein metabolism or function in the disease's pathogenesis. Cerebrospinal fluid (CSF) which surrounds the brain can be used to study changes in neurodegenerative diseases and to identify disease-related mechanisms or neurochemical biomarkers for diagnosis. In the present review, we will give an overview of the current literature on proteomic studies in CSF of FTLD patients. Reports of targeted and unbiased proteomic approaches are included and the results are discussed in regard of their informative value about disease pathology and the suitability to be used as diagnostic biomarkers. Finally, we will give some future perspectives on CSF proteomics and a list of candidate biomarkers which might be interesting for validation in further studies. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.

  • Elevated glial fibrillary acidic protein levels in the cerebrospinal fluid of patients with narcolepsy.

    27 October 2017

    Glial fibrillary acidic protein (GFAP) is an established indicator of astrogliosis. Therefore, variable cerebrospinal fluid (CSF) concentrations of this protein might reflect disease-specific pathologic profiles. In patients with narcolepsy, a loss of hypocretin-1 (hcrt-1) neurons in the brain and low concentrations of hcrt-1 in CSF have been reported. We performed a commercially available enzyme-linked immunosorbent assay to investigate if GFAP also is altered in the CSF of these patients. Here we detected significantly higher CSF levels of GFAP in patients with low hcrt-1 levels, of which the majority had a diagnosis of narcolepsy and cataplexy (NC); however, this finding was not observed in patients with hcrt-1 levels that were within reference range. In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy, and this hypothesis should be investigated in larger studies.

  • Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD.

    17 November 2017

    The loss-of-function mechanism in progranulin (PGRN) mutation carriers makes PGRN an interesting target for upregulation as a therapeutic approach in neurodegenerative diseases like frontotemporal lobar degeneration. This gives rise to several questions: (1) how stable are PGRN levels in blood and cerebrospinal fluid (CSF) in follow-up? (2) Is it necessary to measure PGRN levels in CSF to monitor a therapeutic effect? Therefore, concentrations of PGRN were measured in paired CSF and serum samples of 22 patients with behavioural variant frontotemporal dementia, including one GRN mutation carrier (c.349+1G>C), 16 patients with amyotrophic lateral sclerosis and 17 non-neurodegenerative patients, which included 22 follow-up levels. PGRN levels of 14 patients with isolated dysfunction of the blood-CSF barrier were measured and PGRN was correlated with albumin quotients as a marker for blood-CSF barrier function. The intrathecal fraction of PGRN was calculated on the basis of CSF-to-serum ratios and hydrodynamic properties. Follow-up measurements of CSF and serum PGRN levels did not show any significant change in diagnostic groups. Mean PGRN levels are 35 times higher in blood than in CSF. However, the CSF-to-serum PGRN ratio does not correlate with the albumin quotient even in patients with severe impairment of the blood-CSF barrier. The calculated intrathecal fraction of CSF PGRN levels ranged between 80 and 90 %. Assuming that CSF PGRN is either brain-derived or transported from the vascular compartment via receptor mediated mechanisms, we propose that monitoring CNS specific effects of PGRN modulating drugs should be done in CSF.

  • Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients.

    17 November 2017

    OBJECTIVES: Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). METHODS: In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. RESULTS: Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. CONCLUSIONS: Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

  • Neuroanatomy and Cognition Group

    15 January 2013

    DCN

    Our projects study cognitive/psychiatric disorders and comparative evolutionary neuroscience. We are interested in the relationship between brain structure and function in disease, development and aging - particularly related to language and social cognition.

  • Oxford Epilepsy Research Group

    2 April 2014

    DCN

    We are a forward-looking dynamic group interested in all aspects of clinical and experimental epileptology with an emphasis on clinically relevant research. The Group draws together all relevant disciplines across Oxford University Hospitals and the University of Oxford.

  • Epilepsy Imaging Research Group

    14 February 2013

    FMRIB

    Combining state-of-the-art brain imaging methods, we aim to understand how functional networks in the brain respond and adapt to epilepsy and epilepsy-associated lesions.

  • Neurogenetic Disorders Group

    15 January 2013

    DCN

    Our aim is to elucidate the pathophysiological basis of human neurological disorders from genetic molecular networks to complex neural systems. We achieve this through development of relevant disease models that will then serve as novel and robust platforms for drug discovery.

  • Clinical Ophthalmology Research Group

    15 January 2013

    NLO

    We are developing gene therapy and stem cell treatments for retinal diseases

  • Retinal Neurobiology and Optogenetics Group

    15 January 2013

    NLO

    Our research focuses on light dependent signalling in the retina and brain, including visual and non-visual light detection. We are also examining novel opsin photopigments and exploring their applications to optogenetics.

  • Retinal Degeneration and Gene Identification

    15 January 2013

    NLO

    Our work involves the identification and characterisation of genes that play a role in the retina, including both visual and non-image forming tasks such as the detection of light for the entrainment of the circadian system.

  • Oxford StemBANCC – Stem Cells for Drug Discovery

    5 February 2013

    DCN

    The University of Oxford is the academic lead institution for StemBANCC. This 5-year research programme funded by the Innovative Medicines Initiative (IMI) involving academic and industry partners across 11 countries with the objective of developing human induced pluripotent stem cells as a platform for drug discovery.

  • Molecular Neurodegeneration Research Group

    11 March 2014

    DCN

    Our aim is to understand fundamental biological processes that could inform the development of targeted therapies and innovative biomarkers in neurodegenerative and neurogenetic disorders.