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  • Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

    17 November 2017

    The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

  • Genetics and neurochemical biomarkers in ALS and FTLD

    27 October 2017

    Both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are progressive neurodegenerative diseases. In ALS, neurodegeneration results in progressive paralysis of muscles and finally in respiratory insufficiency. FTLD, on the other hand, progressively affects behavior, speech, and in some cases the motor system. Over recent years, some clinical overlapping of these syndromes with their common histopathology of aggregated TDP-43 in the cytoplasm of neurons resulted in the hypothesis that both syndromes are parts of a clinical as well as pathophysiological continuum. As a first step, mutations of the TDP-43 gene have been identified as possible molecular mechanism. Furthermore, a pathological repeat expansion of chromosome 9 - C9orf72 - is associated with 25-30 percent of all genetically determined cases of ALS and about 11 percent of the FTLD cases in Europe. However, 20% of the sporadic cases also have a C9orf72 expansion. Particularly in asymptomatic mutation carriers and in sporadic cases, the diagnosis at an early stage of the disease and reliable classification of the symptoms of ALS and FTLD is usually difficult. Therefore, it would be desirable to develop reliable and specific biomarkers that allow valid diagnosis and evaluation of prognosis. © Georg Thieme Verlag KG Stuttgart New York.

  • Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration

    27 October 2017

    Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of syndromes with different symptoms. Frontotemporal lobar degeneration is mostly used as a clinical umbrella term for different diseases. In some clinical subtypes of the FTLD spectrum, a close correlation with underlying pathology can be found. Neuroimaging techniques, such as magnetic resonance imaging and position emission tomography help to detect neuroanatomical lesions and therefore obtain relevance for in vivo prediction of neurodegeneration. However, there is still a lack of neurochemical biomarkers helping to differentiate between underlying histopathologies. The following review gives an overview about present neurochemical biomarker studies and perspective approaches in the diagnosis of FTLD. © 2012 by Walter de Gruyter.

  • Enhancing the alignment of the preclinical and clinical stroke recovery research pipeline: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable translational working group.

    23 November 2017

    Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.

  • Modulating hemispheric lateralization by brain stimulation yields gain in mental and physical activity.

    17 November 2017

    Imagery plays an important role in our life. Motor imagery is the mental simulation of a motor act without overt motor output. Previous studies have documented the effect of motor imagery practice. However, its translational potential for patients as well as for athletes, musicians and other groups, depends largely on the transfer from mental practice to overt physical performance. We used bilateral transcranial direct current stimulation (tDCS) over sensorimotor areas to modulate neural lateralization patterns induced by unilateral mental motor imagery and the performance of a physical motor task. Twenty-six healthy older adults participated (mean age = 67.1 years) in a double-blind cross-over sham-controlled study. We found stimulation-related changes at the neural and behavioural level, which were polarity-dependent. Specifically, for the hand contralateral to the anode, electroencephalographic activity induced by motor imagery was more lateralized and motor performance improved. In contrast, for the hand contralateral to the cathode, hemispheric lateralization was reduced. The stimulation-related increase and decrease in neural lateralization were negatively related. Further, the degree of stimulation-related change in neural lateralization correlated with the stimulation-related change on behavioural level. These convergent neurophysiological and behavioural effects underline the potential of tDCS to improve mental and physical motor performance.

  • Subthalamic deep brain stimulation sweet spots and hyperdirect cortical connectivity in Parkinson's disease.

    23 November 2017

    OBJECTIVES: Firstly, to identify subthalamic region stimulation clusters that predict maximum improvement in rigidity, bradykinesia and tremor, or emergence of side-effects; and secondly, to map-out the cortical fingerprint, mediated by the hyperdirect pathways which predict maximum efficacy. METHODS: High angular resolution diffusion imaging in twenty patients with advanced Parkinson's disease was acquired prior to bilateral subthalamic nucleus deep brain stimulation. All contacts were screened one-year from surgery for efficacy and side-effects at different amplitudes. Voxel-based statistical analysis of volumes of tissue activated models was used to identify significant treatment clusters. Probabilistic tractography was employed to identify cortical connectivity patterns associated with treatment efficacy. RESULTS: All patients responded well to treatment (46% mean improvement off medication UPDRS-III [p < 0.0001]) without significant adverse events. Cluster corresponding to maximum improvement in tremor was in the posterior, superior and lateral portion of the nucleus. Clusters corresponding to improvement in bradykinesia and rigidity were nearer the superior border in a further medial and posterior location. The rigidity cluster extended beyond the superior border to the area of the zona incerta and Forel-H2 field. When the clusters where averaged, the coordinates of the area with maximum overall efficacy was X = -10(-9.5), Y = -13(-1) and Z = -7(-3) in MNI(AC-PC) space. Cortical connectivity to primary motor area was predictive of higher improvement in tremor; whilst that to supplementary motor area was predictive of improvement in bradykinesia and rigidity; and connectivity to prefrontal cortex was predictive of improvement in rigidity. INTERPRETATION: These findings support the presence of overlapping stimulation sites within the subthalamic nucleus and its superior border, with different cortical connectivity patterns, associated with maximum improvement in tremor, rigidity and bradykinesia.

  • Improved tractography using asymmetric fibre orientation distributions.

    20 November 2017

    Diffusion MRI allows us to make inferences on the structural organisation of the brain by mapping water diffusion to white matter microstructure. However, such a mapping is generally ill-defined; for instance, diffusion measurements are antipodally symmetric (diffusion along x and -x are equal), whereas the distribution of fibre orientations within a voxel is generally not symmetric. Therefore, different sub-voxel patterns such as crossing, fanning, or sharp bending, cannot be distinguished by fitting a voxel-wise model to the signal. However, asymmetric fibre patterns can potentially be distinguished once spatial information from neighbouring voxels is taken into account. We propose a neighbourhood-constrained spherical deconvolution approach that is capable of inferring asymmetric fibre orientation distributions (A-fods). Importantly, we further design and implement a tractography algorithm that utilises the estimated A-fods, since the commonly used streamline tractography paradigm cannot directly take advantage of the new information. We assess performance using ultra-high resolution histology data where we can compare true orientation distributions against sub-voxel fibre patterns estimated from down-sampled data. Finally, we explore the benefits of A-fods-based tractography using in vivo data by evaluating agreement of tractography predictions with connectivity estimates made using different in-vivo modalities. The proposed approach can reliably estimate complex fibre patterns such as sharp bending and fanning, which voxel-wise approaches cannot estimate. Moreover, histology-based and in-vivo results show that the new framework allows more accurate tractography and reconstruction of maps quantifying (symmetric and asymmetric) fibre complexity.

  • l-Dopa responsiveness is associated with distinctive connectivity patterns in advanced Parkinson's disease.

    23 November 2017

    BACKGROUND: Neuronal loss and dopamine depletion alter motor signal processing between cortical motor areas, basal ganglia, and the thalamus, resulting in the motor manifestations of Parkinson's disease. Dopamine replacement therapy can reverse these manifestations with varying degrees of improvement. METHODS: To evaluate functional connectivity in patients with advanced Parkinson's disease and changes in functional connectivity in relation to the degree of response to l-dopa, 19 patients with advanced Parkinson's disease underwent resting-state functional magnetic resonance imaging in the on-medication state. Scans were obtained on a 3-Tesla scanner in 3 × 3 × 2.5 mm(3) voxels. Seed-based bivariate regression analyses were carried out with atlas-defined basal ganglia regions as seeds, to explore relationships between functional connectivity and improvement in the motor section of the UPDRS-III following an l-dopa challenge. False discovery rate-corrected P was set at < 0.05 for a 2-tailed t test. RESULTS: A greater improvement in UPDRS-III scores following l-dopa administration was characterized by higher resting-state functional connectivity between the prefrontal cortex and the striatum (P = 0.001) and lower resting-state functional connectivity between the pallidum (P = 0.001), subthalamic nucleus (P = 0.003), and the paracentral lobule (supplementary motor area, mesial primary motor, and primary sensory areas). CONCLUSIONS: Our findings show characteristic basal ganglia resting-state functional connectivity patterns associated with different degrees of l-dopa responsiveness in patients with advanced Parkinson's disease. l-Dopa exerts a graduated influence on remapping connectivity in distinct motor control networks, potentially explaining some of the variance in treatment response. © 2017 International Parkinson and Movement Disorder Society.

  • Multiple signals in anterior cingulate cortex.

    23 November 2017

    Activity in anterior cingulate cortex (ACC) has been linked both to commitment to a course of action, even when it is associated with costs, and to exploring or searching for alternative courses of action. Here we review evidence that this is due to the presence of multiple signals in ACC reflecting the updating of beliefs and internal models of the environment and encoding aspects of choice value, including the average value of choices afforded by the environment ('search value'). We contrast this evidence with the influential view that ACC activity is better described as reflecting task difficulty. A consideration of cortical neural network properties explains why ACC may carry such signals and also exhibit sensitivity to task difficulty.

  • Inhibitory engrams in perception and memory.

    20 November 2017

    Nervous systems use excitatory cell assemblies to encode and represent sensory percepts. Similarly, synaptically connected cell assemblies or "engrams" are thought to represent memories of past experience. Multiple lines of recent evidence indicate that brain systems create and use inhibitory replicas of excitatory representations for important cognitive functions. Such matched "inhibitory engrams" can form through homeostatic potentiation of inhibition onto postsynaptic cells that show increased levels of excitation. Inhibitory engrams can reduce behavioral responses to familiar stimuli, thereby resulting in behavioral habituation. In addition, by preventing inappropriate activation of excitatory memory engrams, inhibitory engrams can make memories quiescent, stored in a latent form that is available for context-relevant activation. In neural networks with balanced excitatory and inhibitory engrams, the release of innate responses and recall of associative memories can occur through focused disinhibition. Understanding mechanisms that regulate the formation and expression of inhibitory engrams in vivo may help not only to explain key features of cognition but also to provide insight into transdiagnostic traits associated with psychiatric conditions such as autism, schizophrenia, and posttraumatic stress disorder.

  • FMRIB Plasticity Group

    15 January 2013

    FMRIB

    We study how the brain changes when we learn, as we get older, or when we recover damage such as stroke. We use brain imaging to monitor brain change and we aim to develop new approaches to facilitate learning, recovery and healthy ageing.

  • Translational Image Analysis Group

    16 August 2013

    FMRIB

    Our work focuses on translating imaging analysis methods to better understand processes such as brain maturation and ageing, and with a particular emphasis on neurodegenerative disorders (Alzheimer's, Parkinson's, Huntington's, ALS).

  • FMRI Acquisition and Reconstruction

    15 January 2013

    FMRIB

    We develop image acquisition and reconstruction techniques for functional MRI. These methods aim to provide higher spatial and temporal resolution, as well as greater sensitivity to brain activity.

  • FMRI Physiology

    15 January 2013

    FMRIB

    By understanding more about the BOLD signal that underlies functional MRI signal, we develop new techniques to quantify multiple aspects of brain physiology.

  • Microstructural Imaging

    15 January 2013

    FMRIB

    The fine-scale structure of brain tissue is crucial to neural function and health. We are developing MRI techniques that may enable non-invasive estimates of brain microstructure.

  • MR Spectroscopy

    15 January 2013

    FMRIB

    We develop methods for non-invasively measuring the molecular signatures of the brain in health and pathology.

  • Ultra High-Field MRI Physics

    15 January 2013

    FMRIB

    We develop techniques and hardware on the Centre’s 7 Tesla MRI scanner to offer neuroscientists exciting new possibilities to image the structure, function and biochemistry of the human brain.

  • Multiple Sclerosis Basic and Translational Research Group

    15 January 2013

    DCN

    Our group investigates the role of risk factors in the development of multiple sclerosis through functional genetic and neuro-immunological analyses, with the aim of translating these findings into a clinical utility.