Imperial College London

ProfessorDavidSharp

Faculty of MedicineDepartment of Brain Sciences

Professor of Neurology
 
 
 
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Contact

 

+44 (0)20 7594 7991david.sharp Website

 
 
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Assistant

 

Professor Nick Oliver +44 (0)20 7594 1796

 
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Location

 

E315B - C3NLBurlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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220 results found

Kurtin DL, Violante IR, Zimmerman K, Leech R, Hampshire A, Patel MC, Carmichael DW, Sharp DJ, Li LMet al., 2021, Investigating the interaction between white matter and brain state on tDCS-induced changes in brain network activity, Brain Stimulation, Vol: 14, Pages: 1261-1270, ISSN: 1876-4754

BACKGROUND: Transcranial direct current stimulation (tDCS) is a form of noninvasive brain stimulation whose potential as a cognitive therapy is hindered by our limited understanding of how participant and experimental factors influence its effects. Using functional MRI to study brain networks, we have previously shown in healthy controls that the physiological effects of tDCS are strongly influenced by brain state. We have additionally shown, in both healthy and traumatic brain injury (TBI) populations, that the behavioral effects of tDCS are positively correlated with white matter (WM) structure. OBJECTIVES: In this study we investigate how these two factors, WM structure and brain state, interact to shape the effect of tDCS on brain network activity. METHODS: We applied anodal, cathodal and sham tDCS to the right inferior frontal gyrus (rIFG) of healthy (n = 22) and TBI participants (n = 34). We used the Choice Reaction Task (CRT) performance to manipulate brain state during tDCS. We acquired simultaneous fMRI to assess activity of cognitive brain networks and used Fractional Anisotropy (FA) as a measure of WM structure. RESULTS: We find that the effects of tDCS on brain network activity in TBI participants are highly dependent on brain state, replicating findings from our previous healthy control study in a separate, patient cohort. We then show that WM structure further modulates the brain-state dependent effects of tDCS on brain network activity. These effects are not unidirectional - in the absence of task with anodal and cathodal tDCS, FA is positively correlated with brain activity in several regions of the default mode network. Conversely, with cathodal tDCS during CRT performance, FA is negatively correlated with brain activity in a salience network region. CONCLUSIONS: Our results show that experimental and participant factors interact to have unexpected effects on brain network activity, and that these effects are not fully predictable by studying the fa

Journal article

Evans M, Wade C, Hohenschurz-Schmidt D, Lally P, Ugwudike A, Shah K, Bangerter N, Sharp D, Rice ASCet al., 2021, Magnetic resonance imaging as a biomarker in diabetic and HIV-associated peripheral neuropathy: A systematic review-based narrative, Frontiers in Neuroscience, ISSN: 1662-453X

Background: Peripheral neuropathy can be caused by diabetes mellitus and HIV infection, and often leaves patients with treatment-resistant neuropathic pain. To better treat this condition, we need greater understanding of the pathogenesis, as well as objective biomarkers to predict treatment response. Magnetic resonance imaging (MRI) has a firm place as a biomarker for diseases of the central nervous system (CNS), but until recently has had little role for disease of the peripheral nervous system. Objectives: To review the current state-of-the-art of peripheral nerve MRI in diabetic and HIV symmetrical polyneuropathy. We used systematic literature search methods to identify all studies currently published, using this as a basis for a narrative review to discuss major findings in the literature. We also assessed risk of bias, as well as technical aspects of MRI and statistical analysis. Methods: Protocol was pre-registered on NIHR PROSPERO database. MEDLINE, Web of Science and EMBASE databases were searched from 1946 to 15th August 2020 for all studies investigating either diabetic or HIV neuropathy and MRI, focusing exclusively on studies investigating symmetrical polyneuropathy. The NIH quality assessment tool for observational and cross-sectional cohort studies was used for risk of bias assessment. Results: The search resulted in 18 papers eligible for review, 18 for diabetic neuropathy and 0 for HIV neuropathy. Risk of bias assessment demonstrated that studies generally lacked explicit sample size justifications, and some may be underpowered. Whilst most studies made efforts to balance groups for confounding variables (age, gender, BMI, disease duration), there was lack of consistencybetween studies. Overall, the literature provides convincing evidence that DPN is associated with larger nerve cross sectional area, T2-weighted hyperintense and hypointense lesions, evidence of nerve oedema on Dixon imaging, decreased fractional anisotropy and increased apparent dif

Journal article

Hadi Z, Pondeca YJ, Calzolari E, Chepisheva MK, Rust HM, Sharp DJ, Mahmud MS, Seemungal BMet al., 2021, Vestibular Agnosia Linked to Widespread Abnormality of Functional Brain Networks, BNA 2021, Publisher: SAGE Publications, ISSN: 2398-2128

Conference paper

Zimmerman K, Laverse E, Samra R, Yanez Lopez M, Jolly AE, Bourke NJ, Graham N, Patel MC, Hardy J, Kemp S, Morris HR, Sharp Det al., 2021, White matter abnormalities in active elite adult rugby players, Brain Communications, Vol: 3, Pages: 1-19, ISSN: 2632-1297

The recognition, diagnosis and management of mild traumatic brain injuries is difficult and confusing. It is unclear how the severity and number of injuries sustained relate to brain injuries such as diffuse axonal injury, diffuse vascular injury and progressive neurodegeneration. Advances in neuroimaging techniques enable the investigation of neuropathologies associated with acute and long-term effects of injury. Head injuries are the most commonly reported injury seen during professional rugby. There is increased vigilance for the immediate effects of these injuries in matches, but there has been surprisingly little research investigating the longer-term effects of rugby participation.Here we present a longitudinal observational study investigating the relationship of exposure to rugby participation and sub-acute head injuries in professional adult male and female rugby union and league players using advanced MRI. Diffusion tensor imaging and susceptibility weighted imaging was used to assess white matter structure and evidence of axonal and diffuse vascular injury. We also studied changes in brain structure over time using Jacobian Determinant statistics extracted from serial volumetric imaging. We tested 41 male and 3 female adult elite rugby players, of whom 21 attended study visits after a head injury, alongside 32 non-sporting controls, 15 non-collision-sport athletic controls and 16 longitudinally assessed controls. 18 rugby players participated in the longitudinal arm of the study, with a second visit at least 6 months after their first scan.Neuroimaging evidence of either axonal injury or diffuse vascular injury was present in 23% (10/44) of players. In the non-acutely injured group of rugby players, abnormalities of fractional anisotropy and other diffusion measures were seen. In contrast, non-collision-sport athletic controls were not classified as showing abnormalities. A group level contrast also showed evidence of sub-acute injury using diffusion te

Journal article

Farajzadeh Khosroshahi S, Yin X, Donat C, McGarry A, Yanez Lopez M, Baxan N, Sharp D, Sastre M, Ghajari Met al., 2021, Multiscale modelling of cerebrovascular injury reveals the role of vascular anatomy and parenchymal shear stresses, Scientific Reports, Vol: 11, ISSN: 2045-2322

Neurovascular injury is often observed in traumatic brain injury (TBI). However, the relationship between mechanical forces and vascular injury is still unclear. A key question is whether the complex anatomy of vasculature plays a role in increasing forces in cerebral vessels and producing damage. We developed a high-fidelity multiscale finite element model of the rat brain featuring a detailed definition of the angioarchitecture. Controlled cortical impacts were performed experimentally and in-silico. The model was able to predict the pattern of blood–brain barrier damage. We found strong correlation between the area of fibrinogen extravasation and the brain area where axial strain in vessels exceeds 0.14. Our results showed that adjacent vessels can sustain profoundly different axial stresses depending on their alignment with the principal direction of stress in parenchyma, with a better alignment leading to larger stresses in vessels. We also found a strong correlation between axial stress in vessels and the shearing component of the stress wave in parenchyma. Our multiscale computational approach explains the unrecognised role of the vascular anatomy and shear stresses in producing distinct distribution of large forces in vasculature. This new understanding can contribute to improving TBI diagnosis and prevention.

Journal article

Liu KY, Howard R, Banerjee S, Comas-Herrera A, Goddard J, Knapp M, Livingston G, Manthorpe J, O'Brien JT, Paterson RW, Robinson L, Rossor M, Rowe JB, Sharp DJ, Sommerlad A, Suarez-Gonzalez A, Burns Aet al., 2021, Dementia wellbeing and COVID-19: Review and expert consensus on current research and knowledge gaps, INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, ISSN: 0885-6230

Journal article

Molero Y, Sharp DJ, Onofrio BMD, Larsson H, Fazel Set al., 2021, Psychotropic and pain medication use in individuals with traumatic brain injury-a Swedish total population cohort study of 240 000 persons, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 92, Pages: 519-527, ISSN: 0022-3050

Journal article

Popescu SG, Sharp DJ, Cole JH, Kamnitsas K, Glocker Bet al., 2021, Distributional gaussian process layers for outlier detection in imagesegmentation, Information Processing in Medical Imaging (IPMI) 2021, Publisher: arXiv

We propose a parameter efficient Bayesian layer for hierarchicalconvolutional Gaussian Processes that incorporates Gaussian Processes operatingin Wasserstein-2 space to reliably propagate uncertainty. This directlyreplaces convolving Gaussian Processes with a distance-preserving affineoperator on distributions. Our experiments on brain tissue-segmentation showthat the resulting architecture approaches the performance of well-establisheddeterministic segmentation algorithms (U-Net), which has never been achievedwith previous hierarchical Gaussian Processes. Moreover, by applying the samesegmentation model to out-of-distribution data (i.e., images with pathologysuch as brain tumors), we show that our uncertainty estimates result inout-of-distribution detection that outperforms the capabilities of previousBayesian networks and reconstruction-based approaches that learn normativedistributions.

Conference paper

Duckworth H, Sharp DJ, Ghajari M, 2021, Smoothed particle hydrodynamic modelling of the cerebrospinal fluid for brain biomechanics: accuracy and stability, International Journal for Numerical Methods in Biomedical Engineering, Vol: 37, ISSN: 1069-8299

The Cerebrospinal Fluid (CSF) can undergo shear deformations under head motions. Finite Element (FE) models, which are commonly used to simulate biomechanics of the brain, including traumatic brain injury, employ solid elements to represent the CSF. However, the limited number of elements paired with shear deformations in CSF can decrease the accuracy of their predictions. Large deformation problems can be accurately modelled using the mesh-free Smoothed Particle Hydrodynamics (SPH) method, but there is limited previous work on using this method for modelling the CSF. Here we explored the stability and accuracy of key modelling parameters of an SPH model of the CSF when predicting relative brain/skull displacements in a simulation of an in vivo mild head impact in human. The Moving Least Squares (MLS) SPH formulation and Ogden rubber material model were found to be the most accurate and stable. The strain and strain rate in the brain differed across the SPH and FE models of CSF. The FE mesh anchored the gyri, preventing them from experiencing the level of strains seen in the in vivo brain experiments and predicted by the SPH model. Additionally, SPH showed higher levels of strains in the sulci compared to the FE model. However, tensile instability was found to be a key challenge of the SPH method, which needs to be addressed in future. Our study provides a detailed investigation of the use of SPH and shows its potential for improving the accuracy of computational models of brain biomechanics.

Journal article

Zimmerman K, Kim J, Karton C, Lochhead L, Sharp D, Hoshizaki T, Ghajari Met al., 2021, Player position in American Football influences the magnitude of mechanical strains produced in the location of chronic traumatic encephalopathy pathology: a computational modelling study, Journal of Biomechanics, Vol: 118, ISSN: 0021-9290

American football players are frequently exposed to head impacts, which can cause concussions and may lead to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). Player position appears to influence the risk of concussion but there is limited work on its effect on the risk of CTE. Computational modelling has shown that large brain deformations during head impacts co-localise with CTE pathology in sulci. Here we test whether player position has an effect on brain deformation within the sulci, a possible biomechanical trigger for CTE. We physically reconstructed 148 head impact events from video footage of American Football games. Players were separated into 3 different position profiles based on the magnitude and frequency of impacts. A detailed finite element model of TBI was then used to predict Green-Lagrange strain and strain rate across the brain and in sulci. Using a one-way ANOVA, we found that in positions where players were exposed to large magnitude and low frequency impacts (e.g. defensive back and wide receiver), strain and strain rate across the brain and in sulci were highest. We also found that rotational head motion is a key determinant in producing large strains and strain rates in the sulci. Our results suggest that player position has a significant effect on impact kinematics, influencing the magnitude of deformations within sulci, which spatially corresponds to where CTE pathology is observed. This work can inform future studies investigating different player-position risks for concussion and CTE and guide design of prevention systems.

Journal article

Li LM, Dilley MD, Carson A, Twelftree J, Hutchinson PJ, Belli A, Betteridge S, Cooper PN, Griffin CM, Jenkins PO, Liu C, Sharp DJ, Sylvester R, Wilson MH, Turner MS, Greenwood Ret al., 2021, Management of traumatic brain injury (TBI): a clinical neuroscience-led pathway for the NHS., Clinical medicine (London, England), Vol: 21, Pages: e198-e205, ISSN: 1470-2118

Following hyperacute management after traumatic brain injury (TBI), most patients receive treatment which is inadequate or inappropriate, and delayed. This results in suboptimal rehabilitation outcome and avoidable detrimental chronic effects on patients' recovery. This worsens long-term disability, and magnifies costs to the individual and society. We believe that accurate diagnosis (at the level of pathology, impairment and function) of the causes of disability is a prerequisite for appropriate care and for accessing effective rehabilitation. An expert-led, integrated care pathway is needed to deliver accurate and timely diagnosis and optimal treatment at all stages during a TBI patient's care.We propose the introduction of a specialist interdisciplinary traumatic brain injury team, led by a neurosciences-trained brain injury consultant. This team would engage acutely and for a longer term after TBI to provide accurate diagnoses, which guides subsequent management and rehabilitation. This approach would also encourage more efficient collaboration between research and the clinic. We propose that the current major trauma network is leveraged to introduce and evaluate this proposal. Improvements to patient outcomes through this approach would lead to reduced personal, societal and economic impact of TBI.

Journal article

Ladhani SN, Chow JY, Atkin S, Brown KE, Ramsay ME, Randell P, Sanderson F, Junghans C, Sendall K, Downes R, Sharp D, Graham N, Wingfield D, Howard R, McLaren R, Lang Net al., 2021, Regular mass screening for SARS-CoV-2 infection in care homes already affected by COVID-19 outbreaks: Implications of false positive test results, JOURNAL OF INFECTION, Vol: 82, Pages: 299-301, ISSN: 0163-4453

Journal article

Graham NSN, Junghans C, McLaren R, Randell P, Lang N, Ladhani SN, Sharp DJ, Sanderson Fet al., 2021, High rates of SARS-CoV-2 seropositivity in nursing home residents, Journal of Infection, Vol: 82, Pages: 310-312, ISSN: 0163-4453

Journal article

Bourke N, Yanez-Lopez M, Jenkins P, De Simoni S, Cole J, Lally P, Mallas E, Zhang H, Sharp Det al., 2021, Traumatic brain injury: a comparison of diffusion and volumetric magnetic resonance imaging measures, Brain Communications, Vol: 3, ISSN: 2632-1297

Cognitive impairment following traumatic brain injury remains hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in MRI allow axonal injury to be detected after traumatic brain injury, but the most sensitive approach is unclear. Here we compare the performance of diffusion tensor imaging, neurite orientation dispersion and density-imaging and volumetric measures of brain atrophy in the identification of white matter abnormalities after traumatic brain injury.Thirty patients with moderate-severe traumatic brain injury in the chronic phase and 20 age-matched controls had T1-weighted and diffusion MRI. Neuropsychological tests of processing speed, executive functioning and memory were used to detect cognitive impairment.Extensive abnormalities in neurite density index and orientation dispersion index were observed, with distinct spatial patterns. Fractional anisotropy and mean diffusivity also indicated widespread abnormalities of white matter structure. Neurite density index was significantly correlated with processing speed. Slower processing speed was also related to higher mean diffusivity in the cortico-spinal tracts. Lower white matter volumes were seen following brain injury with greater effect sizes compared to diffusion metrics however volume was not sensitive to changes in cognitive performance.Volume was the most sensitive at detecting change between groups but was not specific for determining relationships with cognition. Abnormalities in fractional anisotropy and mean diffusivity were the most sensitive diffusion measures, however neurite density index and orientation dispersion index may be more spatially specific. Lower neurite density index may be a useful metric for examining slower processing speed.

Journal article

Tenovuo O, Diaz-Arrastia R, Goldstein LE, Sharp DJ, van der Naalt J, Zasler NDet al., 2021, Assessing the Severity of Traumatic Brain Injury-Time for a Change?, JOURNAL OF CLINICAL MEDICINE, Vol: 10

Journal article

Donat C, Yanez Lopez M, Sastre M, Baxan N, Goldfinger M, Seeamber R, Mueller F, Davies P, Hellyer P, Siegkas P, Gentleman S, Sharp D, Ghajari Met al., 2021, From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 70-91, ISSN: 0006-8950

The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a Controlled Cortical Impact, mild and moderate injuries(1 and 2 mm) were performed. Focal and axonal injuries were quantified withvolumetric and diffusion 9.4T MRI two weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters,along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes.The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in segments of the corpus callosum predicted to have a high strain, indicating white matter changes. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning

Journal article

Mallas E-J, De Simoni S, Scott G, Jolly A, Hampshire A, Li L, Bourke N, Roberts S, Gorgoraptis N, Sharp Det al., 2021, Abnormal dorsal attention network activation in memory impairment after traumatic brain injury, Brain: a journal of neurology, Vol: 144, Pages: 114-127, ISSN: 0006-8950

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injurypatients we examined whether: i) impairments in memory encoding are associated with abnormal brain activation in these networks; ii) whether changes in this brain activity predict subsequent memory retrieval; and iii) whether abnormal white matter integrity underpinningfunctional networks is associated with impaired subsequent memory. 35 patients with moderate-severetraumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy controls underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network.Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal

Journal article

Calzolari E, Chepisheva M, Smith RM, Hellyer PJ, Tahtis V, Arshad Q, Jolly A, Mahmud M, Wilson M, Rust H, Sharp DJ, Seemungal BMet al., 2021, Vestibular agnosia in traumatic brain injury and its link to imbalance, Brain, Vol: 144, Pages: 128-143, ISSN: 0006-8950

Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understoodfeature in traumatic brain injury patients. Damage to the inner ear, nerve, brainstem, cerebellumand cerebral hemispheres may all affect vestibular functioning, hence, a multi-level assessment– from reflex to perception – is required. In a previous report, postural instability was thecommonest neurological feature in ambulating acute traumatic brain injury patients. We alsofrequently observe, during ward assessment of acute traumatic brain injury patients withcommon inner ear conditions and a related vigorous vestibular-ocular reflex nystagmus, a lossof vertigo sensation, suggesting a “vestibular agnosia”. Vestibular agnosia patients were alsomore unbalanced, however the link between vestibular agnosia and imbalance was confoundedby the presence of inner ear conditions. We investigated the brain mechanisms of imbalance inacute traumatic brain injury, its link with vestibular agnosia, and potential clinical impact, byprospective laboratory assessment of vestibular function, from reflex to perception, in patientswith preserved peripheral vestibular function. Assessment included vestibular-reflex function;vestibular-perception by participants’ report of their passive yaw rotations in the dark;objective balance via posturography; subjective symptoms via questionnaires; and structuralneuroimaging. We prospectively screened 918 acute admissions, assessed 146 and recruited37. Compared to 37 matched controls, patients showed elevated vestibular-perceptualthresholds (patients 12.92°/s vs. 3.87°/s) but normal vestibular-ocular reflex thresholds(patients 2.52°/s vs. 1.78°/s). Patients with elevated vestibular-perceptual thresholds (3standard deviations above controls’ average), were designated as having vestibular agnosia,and displayed worse posturography than non-vestibular-agnosia patients, despite no differencein vestibular symptom sc

Journal article

Jolly AE, Balaet M, Azor A, Friedland D, Sandrone S, Graham NSN, Zimmerman K, Sharp DJet al., 2021, Detecting axonal injury in individual patients after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 92-113, ISSN: 0006-8950

Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence o

Journal article

Popescu S, Sharp D, Cole J, Glocker Bet al., 2020, Decoupled Sparse Gaussian Processes Components: Separating Decision Making from Data Manifold Fitting, Third Symposium on Advances in Approximate Bayesian Inference

Conference paper

Cooper N, Morrison MA, Vladescu C, Hart ACJ, Paul D, Malik A, Young T, Luqmani A, Atta M, Sharp DJ, Bussel JB, Waldman ADet al., 2020, Identification of occult cerebral microbleeds in adults with immune thrombocytopenia, Blood, Vol: 136, Pages: 2875-2880, ISSN: 0006-4971

Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10−6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.

Journal article

Graham NSN, Jolly A, Zimmerman K, Bourke NJ, Scott G, Cole JH, Schott JM, Sharp DJet al., 2020, Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury, Brain: a journal of neurology, Vol: 143, Pages: 3685-3698, ISSN: 0006-8950

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or ima

Journal article

Li H, Barnaghi P, Skillman S, Sharp D, Nilforooshan R, Rostill Het al., 2020, Machine learning for risk analysis of Urinary Tract Infection in people with dementia, Publisher: arXiv

The Urinary Tract Infections (UTIs) are one of the top reasons for unplannedhospital admissions in people with dementia, and if detected early, they can betimely treated. However, the standard UTI diagnosis tests, e.g. urine tests,will be only taken if the patients are clinically suspected of having UTIs.This causes a delay in diagnosis and treatment of the conditions and in somecases like people with dementia, the symptoms can be difficult to observe.Delay in detection and treatment of dementia is one of the key reasons forunplanned hospital admissions in people with dementia. To address these issues,we have developed a technology-assisted monitoring system, which is a Class 1medical device. The system uses off-the-shelf and low-cost in-home sensorydevices to monitor environmental and physiological data of people with dementiawithin their own homes. We have designed a machine learning model to use thedata and provide risk analysis for UTIs. We use a semi-supervised learningmodel which leverage the environmental data, i.e. the data collected from themotion sensors, smart plugs and network-connected body temperature monitoringdevices in the home, to detect patterns that can show the risk of UTIs. Sincethe data is noisy and partially labelled, we combine the neural networks andprobabilistic neural networks to train an auto-encoder, which is to extract thegeneral representation of the data. We will demonstrate our smart homemanagement by videos/online, and show how our model can pick up the UTI relatedpatterns.

Working paper

Graham NSN, Zimmerman KA, Bertolini G, Magnoni S, Oddo M, Zetterberg H, Moro F, Novelli D, Heslegrave A, Chieregato A, Fainardi E, Fleming JM, Garbero E, Abed-Maillard S, Gradisek P, Bernini A, Sharp DJet al., 2020, Multicentre longitudinal study of fluid and neuroimaging BIOmarkers of AXonal injury after traumatic brain injury: the BIO-AX-TBI study protocol., BMJ Open, Vol: 10, Pages: 1-9, ISSN: 2044-6055

INTRODUCTION AND AIMS: Traumatic brain injury (TBI) often results in persistent disability, due particularly to cognitive impairments. Outcomes remain difficult to predict but appear to relate to axonal injury. Several new approaches involving fluid and neuroimaging biomarkers show promise to sensitively quantify axonal injury. By assessing these longitudinally in a large cohort, we aim both to improve our understanding of the pathophysiology of TBI, and provide better tools to predict clinical outcome. METHODS AND ANALYSIS: BIOmarkers of AXonal injury after TBI is a prospective longitudinal study of fluid and neuroimaging biomarkers of axonal injury after moderate-to-severe TBI, currently being conducted across multiple European centres. We will provide a detailed characterisation of axonal injury after TBI, using fluid (such as plasma/microdialysate neurofilament light) and neuroimaging biomarkers (including diffusion tensor MRI), which will then be related to detailed clinical, cognitive and functional outcome measures. We aim to recruit at least 250 patients, including 40 with cerebral microdialysis performed, with serial assessments performed twice in the first 10 days after injury, subacutely at 10 days to 6 weeks, at 6 and 12 months after injury. ETHICS AND DISSEMINATION: The relevant ethical approvals have been granted by the following ethics committees: in London, by the Camberwell St Giles Research Ethics Committee; in Policlinico (Milan), by the Comitato Etico Milano Area 2; in Niguarda (Milan), by the Comitato Etico Milano Area 3; in Careggi (Florence), by the Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana, Sezione area vasta centro; in Trento, by the Trento Comitato Etico per le Sperimentazioni Cliniche, Azienda Provinciale per i Servizi Sanitari della Provincia autonoma di Trento; in Lausanne, by the Commission cantonale d'éthique de la recherche sur l'être humain; in Ljubljana, by the National Medical

Journal article

Li B, Tan H, Jenkins D, Srinivasa Raghavan V, Gil Rosa B, Guder F, Pan G, Yeatman E, Sharp Det al., 2020, Clinical detection of neurodegenerative blood biomarkers using graphene immunosensor, Carbon, Vol: 168, Pages: 144-162, ISSN: 0008-6223

Accurate detection of blood biomarkers related to neurodegenerative diseases could provide a shortcut to identifying early stage patients before the onset of symptoms. The specificity, selectivity and operational requirements of the current technologies, however, preclude their use in the primary clinical setting for early detection. Graphene, an emerging 2D nanomaterial, is a promising candidate for biosensing which has the potential to meet the performance requirements and enable cost-effective, portable and rapid diagnosis. In this review, we compare graphene-based immunosensing technologies with conventional enzyme-linked immunosorbent assays and cutting-edge single molecule array techniques for the detection of blood-based neurodegenerative biomarkers. We cover the progress in electrical, electrochemical and optical graphene-based immunosensors and outline the barriers that slow or prevent the adoption of this emerging technology in primary clinical settings. We also highlight the possible solutions to overcome these barriers with an outlook on the future of the promising, graphene immunosensor technology.

Journal article

Popescu S, Sharp D, Cole J, Glocker Bet al., 2020, Hierarchical Gaussian processes with Wasserstein-2 kernels, Publisher: arXiv

We investigate the usefulness of Wasserstein-2 kernels in the context ofhierarchical Gaussian Processes. Stemming from an observation that stackingGaussian Processes severely diminishes the model's ability to detect outliers,which when combined with non-zero mean functions, further extrapolates lowvariance to regions with low training data density, we posit that directlytaking into account the variance in the computation of Wasserstein-2 kernels isof key importance towards maintaining outlier status as we progress through thehierarchy. We propose two new models operating in Wasserstein space which canbe seen as equivalents to Deep Kernel Learning and Deep GPs. Through extensiveexperiments, we show improved performance on large scale datasets and improvedout-of-distribution detection on both toy and real data.

Working paper

Crone MA, Priestman M, Ciechonska M, Jensen K, Sharp DJ, Anand A, Randell P, Storch M, Freemont PSet al., 2020, A role for Biofoundries in rapid development and validation of automated SARS-CoV-2 clinical diagnostics (vol 11, 4464, 2020), NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723

Journal article

Deb S, Crawford M, Sharp D, Leeson V, Aimola L, Li L, Weaver T, Bodani M, Bassett Pet al., 2020, Risperidone versus placebo for aggression following traumatic brain injury: a feasibility randomised controlled trial, BMJ Open, Vol: 10, ISSN: 2044-6055

Objectives: To conduct a feasibility randomised controlled trial of risperidone for the treatment of aggression in adults with traumatic brain injury (TBI).Design: Multi-centre, parallel design, placebo controlled (1:1 ratio) double-blind feasibility trial with an embedded process evaluation. No statistical comparison was performed between the two study groups.Setting Four neuropsychiatric and neurology outpatient clinics in London and Kent, UK. Participants Our aim was to recruit 50 TBI patients over 18 months. Follow up participants at 12 weeks using a battery of assessment scales to measure changes in aggressive behaviour (MOAS-primary outcome, IRQ) as well as global functioning (GOS-E, CGI) and quality of life (EQ-5D-5L, SF-12), mental health (HADS) and medication adverse effects (UKU).Results: Six participants were randomised to the active arm of the trial and eight to the placebo arm over a 10-month period (28% of our target). Two participants withdrew because of adverse events. Twelve out of 14 (85.7%) patients completed a follow up assessment at 12 weeks. At follow up, the scores of all outcome measures improved in both groups. Placebo group showed numerically better score change according to the primary outcome MOAS. No severe adverse events were reported. The overall rate of adverse events remained low. Data from the process evaluation suggest that existence of specialised TBI Follow-up clinics, availability of a dedicated database of TBI patients’ clinical details, simple study procedures and regular support to participants would enhance recruitment and retention in the trial. Feedback from participants showed that once in the study, they did not find the trial procedure onerous.Conclusions: It was not feasible to conduct a successful randomised trial of risperidone versus placebo for post-TBI aggression using the methods we deployed in this study. It is not possible to draw any definitive conclusion about risperidone’s efficacy from such a s

Journal article

Crone M, Priestman M, Ciechonska M, Jensen K, Sharp D, Anand A, Randell P, Storch M, Freemont Pet al., 2020, A role for Biofoundries in rapid development and validation of automated SARS-CoV-2 clinical diagnostics, Nature Communications, Vol: 11, Pages: 1-11, ISSN: 2041-1723

The SARS-CoV-2 pandemic has shown how a rapid rise in demand for patient and community sample testing can quickly overwhelm testing capability globally. With most diagnostic infrastructure dependent on specialized instruments, their exclusive reagent supplies quickly become bottlenecks, creating an urgent need for approaches to boost testing capacity. We address this challenge by refocusing the London Biofoundry onto the development of alternative testing pipelines. Here, we present a reagent-agnostic automated SARS-CoV-2 testing platform that can be quickly deployed and scaled. Using an in-house-generated, open-source, MS2-virus-like particle (VLP) SARS-CoV-2 standard, we validate RNA extraction and RT-qPCR workflows as well as two detection assays based on CRISPR-Cas13a and RT-loop-mediated isothermal amplification (RT-LAMP). In collaboration with an NHS diagnostic testing lab, we report the performance of the overall workflow and detection of SARS-CoV-2 in patient samples using RT-qPCR, CRISPR-Cas13a, and RT-LAMP. The validated RNA extraction and RT-qPCR platform has been installed in NHS diagnostic labs, increasing testing capacity by 1000 samples per day.

Journal article

Laverse E, Guo T, Zimmerman K, Foiani MS, Velani B, Morrow P, Adejuwon A, Bamford R, Underwood N, George J, Brooke D, OBrien K, Cross MJ, Kemp SPT, Heslegrave AJ, Hardy J, Sharp DJ, Zetterberg H, Morris HRet al., 2020, Plasma glial fibrillary acidic protein and neurofilament light chain, but not tau, are biomarkers of sports-related mild traumatic brain injury, Brain Communications, Vol: 2, Pages: 1-10, ISSN: 2632-1297

Mild traumatic brain injury is a relatively common event in contact sports and there is increasing interest in the long-term neurocognitive effects. The diagnosis largely relies on symptom reporting and there is a need for objective tools to aid diagnosis and prognosis. There are recent reports that blood biomarkers could potentially help triage patients with suspected injury and normal CT findings. We have measured plasma concentrations of glial and neuronal proteins and explored their potential in the assessment of mild traumatic brain injury in contact sport.We recruited a prospective cohort of active male rugby players, who had pre-season baseline plasma sampling. From this prospective cohort, we recruited 25 players diagnosed with mild traumatic brain injury. We sampled post-match rugby players without head injuries as post-match controls. We measured plasma neurofilament light chain, tau and glial fibrillary acidic protein levels using ultrasensitive single molecule array technology. The data was analysed at the group and individual player level.Plasma glial fibrillary acidic protein concentration was significantly increased 1-hour post-injury in mild traumatic brain injury cases compared to the non-injured group (p = 0.017). Pairwise comparison also showed that glial fibrillary acidic protein levels were higher in players after a head injury in comparison to their pre-season levels at both 1-hour and 3 to 10-days post-injury time points (p = 0.039 and 0.040, respectively). There was also an increase in neurofilament light chain concentration in brain injury cases compared to the pre-season levels within the same individual at both time points (p = 0.023 and 0.002, respectively). Tau was elevated in both the non-injured control group and the 1-hour post-injury group compared to pre-season levels (p = 0.007 and 0.015, respectively). Furthermore, receiver operating characteristic analysis showed that glial

Journal article

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