Imperial College London

ProfessorDavidSharp

Faculty of MedicineDepartment of Brain Sciences

Professor of Neurology
 
 
 
//

Contact

 

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

 
 
//

Location

 

E315B - C3NLBurlington DanesHammersmith Campus

//

Summary

 

Publications

Publication Type
Year
to

167 results found

Gorgoraptis N, Li LM, Whittington A, Zimmerman KA, Maclean LM, McLeod C, Ross E, Heslegrave A, Zetterberg H, Passchier J, Matthews PM, Gunn RN, McMillan TM, Sharp DJet al., 2019, In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury., Sci Transl Med, Vol: 11

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1-42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.

Journal article

Jolly AE, Raymont V, Cole JH, Whittington A, Scott G, De Simoni S, Searle G, Gunn RN, Sharp DJet al., 2019, Dopamine D2/D3 receptor abnormalities after traumatic brain injury and their relationship to post-traumatic depression, NeuroImage: Clinical, Vol: 24, ISSN: 2213-1582

ObjectiveTo investigate dopamine D2/D3 receptor availability following traumatic brain injury (TBI) and their relationship to the presence of DSM-IV Major Depressive Disorder (MDD) and patterns of axonal injury.MethodsTwelve moderate-severe TBI patients and 26 controls were imaged using [11C]PHNO positron emission tomography (PET) and structural magnetic resonance imaging (MRI). TBI patients and a second group of 32 controls also underwent diffusion tensor imaging (DTI) and neuropsychological assessment. Patients included six with post-injury MDD (TBI-MDD) and six without (TBI-NON). Non-displaceable binding potential (BPND) [11C]PHNO values were used to index D2/D3 receptor availability, and were calculated using a reference region procedure. Differences in BPND were examined using voxelwise and region-of-interest analyses. White matter microstructure integrity, quantified by fractional anisotropy (FA), was assessed and correlated with BPND.ResultsLower [11C]PHNO BPND was found in the caudate across all TBI patients when compared to controls. Lower [11C]PHNO BPND was observed in the caudate of TBI-MDD patients and increased [11C]PHNO BPND in the Amygdala of TBI-NON patients compared to controls. There were no significant differences in [11C]PHNO BPND between TBI-MDD and TBI-NON patients. Furthermore, DTI provided evidence of axonal injury following TBI. The uncinate fasciculus and cingulum had abnormally low FA, with the uncinate particularly affected in TBI-MDD patients. Caudate [11C]PHNO BPND correlated with FA within the nigro-caudate tract.Conclusions[11C]PHNO BPND is abnormal following TBI, which indicates post-traumatic changes in D2/D3 receptors. Patterns of [11C]PHNO BPND seen in patients with and without MDD suggest that further research would be beneficial to determine whether the use of dopaminergic treatment might be effective in the treatment of post-traumatic depression.

Journal article

Li L, Violante I, Zimmerman K, Leech R, Hampshire A, Patel M, Opitz A, McArthur D, Carmichael D, Sharp DJet al., Traumatic axonal injury influences the cognitive effect of non-invasive brain stimulation, Brain, ISSN: 1460-2156

Non-invasive brain stimulation has been widely investigated for as a potentialtreatment for a range of neurological and psychiatric conditions, including braininjury. However, the behavioural effects of brain stimulation are very variable, forreasons that are poorly understood. This is a particular challenge for traumatic braininjury, where patterns of damage and their clinical effects are heterogenous. Here wetest the hypothesis that the response to transcranial direct current stimulationfollowing traumatic brain injury is dependent on white matter damage within thestimulated network. We used a novel simultaneous stimulation-MRI protocolapplying anodal, cathodal and sham stimulation to 24 healthy and 35 moderate/severetraumatic brain injury patients. Stimulation was applied to the right inferior frontalgyrus/anterior insula node of the Salience Network, which was targeted because ourprevious work had shown its importance to executive function. Stimulation wasapplied during performance of the Stop Signal Task, which assesses responseinhibition, a key component of executive function. Structural MRI was used to assessthe extent of brain injury, including diffusion MRI assessment of post-traumaticaxonal injury. Functional MRI, which was simultaneously acquired to delivery ofstimulation, assessed the effects of stimulation on cognitive network function. Anodalstimulation improved response inhibition in control participants, an effect that was notobserved in the patient group. The extent of traumatic axonal injury within theSalience Network strongly influenced the behavioural response to stimulation.Increasing damage to the tract connecting the stimulated right inferior frontalgyrus/anterior insula to the rest of the SN was associated with reduced beneficialeffects of stimulation. In addition, anodal stimulation normalised Default ModeNetwork activation in patients with poor response inhibition, suggesting thatstimulation modulates communication between the networks invo

Journal article

Gorgoraptis N, Zaw-Linn J, Feeney C, Tenorio-Jimenez C, Niemi M, Malik A, Ham T, Goldstone AP, Sharp DJet al., 2019, Cognitive impairment and health- related quality of life following traumatic brain injury, Journal of Alzheimer's Disease, Vol: 44, Pages: 321-331, ISSN: 1387-2877

BACKGROUNDCognitive impairment is a common and disabling consequence of traumatic brain injury (TBI) but its impact on health-related quality of life is not well understood.OBJECTIVETo investigate the relationship between cognitive impairment and health-related quality of life (HRQoL) after TBI.METHODSRetrospective, cross-sectional study of a specialist TBI outpatient clinic patient sample. Outcome measures: Addenbrooke's Cognitive Examination Tool - Revised (ACE-R), and SF-36 quality of life, Beck Depression Inventory II (BDI-II), Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) questionnaires.RESULTS240 adults were assessed: n = 172 (71.7% ) moderate-severe, 41 (23.8% ) mild, 27 (11.3% ) symptomatic TBI, 174 (72.5% ) male, median age (range): 44 (22-91) years. TBI patients reported poorer scores on all domains of SF-36 compared to age-matched UK normative data. Cognitively impaired patients reported poorer HRQoL on the physical, social role and emotional role functioning, and mental health domains. Cognitive impairment predicted poorer HRQoL on the social and emotional role functioning domains, independently of depressive symptoms, sleep disturbance, daytime sleepiness and TBI severity. Mediation analysis revealed that the effect of depressive symptoms on the emotional role functioning domain of HRQoL was partially mediated by cognitive dysfunction.CONCLUSIONCognitive impairment is associated with worse health-related quality of life after TBI and partially mediates the effect of depressive symptoms on emotional role functioning.

Journal article

Jenkins PO, De Simoni S, Bourke NJ, Fleminger J, Scott G, Towey DJ, Svensson W, Khan S, Patel MC, Greenwood R, Friedland D, Hampshire A, Cole JH, Sharp DJet al., 2019, Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging, Brain, ISSN: 1460-2156

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03

Journal article

Molero Y, Larsson H, D'Onofrio BM, Sharp DJ, Fazel Set al., 2019, Associations between gabapentinoids and suicidal behaviour, unintentional overdoses, injuries, road traffic incidents, and violent crime: population based cohort study in Sweden, BMJ, ISSN: 0959-8138

OBJECTIVE: To examine associations between gabapentinoids and adverse outcomes related to coordination disturbances (head or body injuries, or both and road traffic incidents or offences), mental health (suicidal behaviour, unintentional overdoses), and criminality. DESIGN: Population based cohort study. SETTING: High quality prescription, patient, death, and crime registers, Sweden. PARTICIPANTS: 191 973 people from the Swedish Prescribed Drug Register who collected prescriptions for gabapentinoids (pregabalin or gabapentin) during 2006 to 2013. MAIN OUTCOME MEASURES: Primary outcomes were suicidal behaviour, unintentional overdoses, head/body injuries, road traffic incidents and offences, and arrests for violent crime. Stratified Cox proportional hazards regression was conducted comparing treatment periods with non-treatment periods within an individual. Participants served as their own control, thus accounting for time invariant factors (eg, genetic and historical factors), and reducing confounding by indication. Additional adjustments were made by age, sex, comorbidities, substance use, and use of other antiepileptics. RESULTS: During the study period, 10 026 (5.2%) participants were treated for suicidal behaviour or died from suicide, 17 144 (8.9%) experienced an unintentional overdose, 12 070 (6.3%) had a road traffic incident or offence, 70 522 (36.7%) presented with head/body injuries, and 7984 (4.1%) were arrested for a violent crime. In within-individual analyses, gabapentinoid treatment was associated with increased hazards of suicidal behaviour and deaths from suicide (age adjusted hazard ratio 1.26, 95% confidence interval 1.20 to 1.32), unintentional overdoses (1.24, 1.19 to 1.28), head/body injuries (1.22, 1.19 to 1.25), and road traffic incidents and offences (1.13, 1.06 to 1.20). Associations with arrests for violent crime were less clear (1.04, 0.98 to 1.11). When the drugs were examined separately, pregabalin was

Journal article

Hughes SW, Hellyer PJ, Sharp DJ, Newbould RD, Patel MC, Strutton PHet al., 2019, Diffusion tensor imaging reveals changes in microstructural integrity along compressed nerve roots that correlate with chronic pain symptoms and motor deficiencies in elderly stenosis patients, NeuroImage: Clinical, Vol: 23, ISSN: 2213-1582

Age-related degenerative changes in the lumbar spine frequently result in nerve root compression causing severe pain and disability. Given the increasing incidence of lumbar spinal disorders in the aging population and the discrepancies between the use of current diagnostic imaging tools and clinical symptoms, novel methods of nerve root assessment are needed. We investigated elderly patients with stenosis at L4-L5 or L5-S1 levels. Diffusion tensor imaging (DTI) was used to quantify microstructure in compressed L5 nerve roots and investigate relationships to clinical symptoms and motor neurophysiology. DTI metrics (i.e. FA, MD, AD and RD) were measured at proximal, mid and distal segments along compressed (i.e. L5) and intact (i.e. L4 or S1) nerve roots. FA was significantly reduced in compressed nerve roots and MD, AD and RD were significantly elevated in the most proximal segment of the nerve root studied. FA was significantly correlated with electrophysiological measures of root function: minimum F-wave latency and peripheral motor conduction time (PMCT). In addition, FA along the compressed root also correlated with leg pain and depression score. There was also a relationship between RD and anxiety, leg pain and disability score and AD correlated with depression score. Taken together, these data show that DTI metrics are sensitive to nerve root compression in patients with stenosis as a result of age-related lumbar degeneration. Critically, they show that the changes in microstructural integrity along compressed L5 nerve roots are closely related to a number of clinical symptoms associated with the development of chronic pain as well as neurophysiological assessments of motor function. These inherent relationships between nerve root damage and phenotype suggest that the use DTI is a promising method as a way to stratify treatment selection and predict outcomes.

Journal article

Underwood J, de francesco D, Cole JH, Caan MWA, Van Zoest RA, Schmand BA, Sharp D, Sabin CA, Reiss P, Winston Aet al., 2019, Validation of a novel multivariate method of defining HIV-associated cognitive impairment, Open Forum Infectious Diseases, ISSN: 2328-8957

BackgroundThe optimum method of defining cognitive impairment in virally suppressed people-living-with-HIV is unknown. We evaluated the relationships between cognitive impairment, including using a novel multivariate method (NMM), patient reported outcome measures (PROMs) and neuroimaging markers of brain structure across three cohorts.MethodsDifferences in the prevalence of cognitive impairment, PROMs and neuroimaging data from the COBRA, CHARTER and POPPY cohorts (total n=908) were determined between HIV-positive participants with and without cognitive impairment defined using the HIV-associated neurocognitive disorders (HAND), global deficit score (GDS) and NMM criteria.ResultsThe prevalence of cognitive impairment varied by up to 27% between methods used to define impairment (e.g. 48% for HAND vs. 21% for NMM in the CHARTER study). Associations between objective cognitive impairment and subjective cognitive complaints were generally weak. Physical and mental health summary scores (SF-36) were lowest for NMM-defined impairment (p’s<0.05).There were no differences in brain volumes or cortical thickness between participants with and without cognitive impairment defined using the HAND and GDS measures. In contrast, those identified with cognitive impairment by the NMM had reduced mean cortical thickness in both hemispheres (p’s<0.05), as well as smaller brain volumes (p<0.01). The associations with measures of white matter microstructure and brain-predicted age were generally weaker.ConclusionDifferent methods of defining cognitive impairment identify different people with varying symptomatology and measures of brain injury. Overall, NMM-defined impairment was associated with most neuroimaging abnormalities and poorer self-reported health status. This may be due to the statistical advantage of using a multivariate approach.

Journal article

Underwood J, De Francesco D, Cole J, Wit F, Sharp D, Sabin C, Reiss P, Winston Aet al., 2019, Antiretroviral central nervous system toxicity, British HIV Association, Publisher: WILEY, Pages: 36-36, ISSN: 1464-2662

Conference paper

Siegkas P, Sharp D, Ghajari M, 2019, The traumatic brain injury mitigation effects of a new viscoelastic add-on liner, Scientific Reports, Vol: 9, ISSN: 2045-2322

Traumatic brain injury (TBI) affects millions of people worldwide with significant personal and social consequences. New materials and methods offer opportunities for improving designs of TBI prevention systems, such as helmets. We combined empirical impact tests and computational modelling to test the effectiveness of new viscoelastic add-on components in decreasing biomechanical forces within the brain during helmeted head impacts. Motorcycle helmets with and without the viscoelastic components were fitted on a head/neck assembly and were tested under oblique impact to replicate realistic accident conditions. Translational and rotational accelerations were measured during the tests. The inclusion of components reduced peak accelerations, with a significant effect for frontal impacts and a marginal effect for side and rear impacts. The head accelerations were then applied on a computational model of TBI to predict strain and strain-rate across the brain. The presence of viscoelastic components in the helmet decreased strain and strain-rate for frontal impacts at low impact speeds. The effect was less pronounced for front impact at high speeds and for side and rear impacts. This work shows the potential of the viscoelastic add-on components as lightweight and cost-effective solutions for enhancing helmet protection and decreasing strain and strain-rate across the brain during head impacts.

Journal article

Sridharan S, Raffel J, Nandoskar A, Record C, Brooks DJ, Owen D, Sharp D, Muraro PA, Gunn R, Nicholas Ret al., Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter, Molecular Imaging and Biology, ISSN: 1536-1632

Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in

Journal article

Li L, Ribeiro Violante I, Leech R, Ross E, Hampshire A, Opitz A, Rothwell J, Carmichael D, Sharp Det al., 2019, Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation, Human Brain Mapping, Vol: 40, Pages: 904-915, ISSN: 1065-9471

Despite its widespread use in cognitive studies, there is still limited understanding of whether and how transcranial direct current stimulation (tDCS) modulates brain network function. To clarify its physiological effects, we assessed brain network function using functional magnetic resonance imaging (fMRI) simultaneously acquired during tDCS stimulation. Cognitive state was manipulated by having subjects perform a Choice Reaction Task or being at “rest.” A novel factorial design was used to assess the effects of brain state and polarity. Anodal and cathodal tDCS were applied to the right inferior frontal gyrus (rIFG), a region involved in controlling activity large‐scale intrinsic connectivity networks during switches of cognitive state. tDCS produced widespread modulation of brain activity in a polarity and brain state dependent manner. In the absence of task, the main effect of tDCS was to accentuate default mode network (DMN) activation and salience network (SN) deactivation. In contrast, during task performance, tDCS increased SN activation. In the absence of task, the main effect of anodal tDCS was more pronounced, whereas cathodal tDCS had a greater effect during task performance. Cathodal tDCS also accentuated the within‐DMN connectivity associated with task performance. There were minimal main effects of stimulation on network connectivity. These results demonstrate that rIFG tDCS can modulate the activity and functional connectivity of large‐scale brain networks involved in cognitive function, in a brain state and polarity dependent manner. This study provides an important insight into mechanisms by which tDCS may modulate cognitive function, and also has implications for the design of future stimulation studies.

Journal article

De Francesco D, Wit FW, Burkle A, Oehlke S, Kootstra NA, Winston A, Franceschi C, Garagnani P, Pirazzini C, Libert C, Grune T, Weber D, Jansen EHJM, Sabin CA, Reiss P, Reiss P, Winston A, Wit FW, Prins M, van der Loeff MFS, Schouten J, Schmand B, Geurtsen GJ, Sharp DJ, Caan MWA, Majoie C, Villaudy J, Berkhout B, Kootstra NA, Gisslen M, Pasternak A, Sabin CA, Guaraldi G, Burkle A, Libert C, Franceschi C, Kalsbeek A, Fliers E, Hoeijmakers J, Pothof J, van der Valk M, Bisschop PH, Portegies P, Zaheri S, Burger D, Cole JH, Biirkle A, Zikkenheiner W, Janssen FR, Underwood J, Kooij KW, van Zoest RA, Doyle N, van der Loeff MS, Schmand BA, Verheij E, Verboeket SO, Elsenga BC, Hillebregt MMJ, Ruijs YMC, Benschop DP, Tembo L, McDonald L, Stott M, Legg K, Lovell A, Erlwein O, Kingsley C, Norsworthy P, Mullaney S, Kruijer T, del Grande L, Olthof V, Visser GR, May L, Verbraak F, Demirkaya N, Visser I, Majoie CBLM, Su T, Leech R, Huguet J, Frankin E, van der Kuyl A, Weijer K, Siteur-Van Rijnstra E, Harskamp-Holwerda AM, Maurer I, Ruiz MMM, Girigorie AF, Boeser-Nunnink B, Kals-Beek A, Bisschop PHLT, de Graaff-Teulen M, Dewaele S, Garagnani P, Pirazzini C, Capri M, Dall'Olio F, Chiricolo M, Salvioli S, Fuchs D, Zetterberg H, Weber D, Grune T, Jansen EHJM, De Francesco D, Sindlinger T, Oehlke Set al., 2019, Do people living with HIV experience greater age advancement than their HIV-negative counterparts?, AIDS, Vol: 33, Pages: 259-268, ISSN: 0269-9370

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH)may show signs of premature/accentuated aging. We compared established biomarkersof aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors,and explored factors associated with biological age advancement.Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors.Methods: Biological age was estimated using a validated algorithm based on 10biomarkers. Associations between ‘age advancement’ (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitisB (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression.Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2(11.6–14.9) years] and HIV-negative [5.5 (3.8–7.2) years] COBRA participants comparedwith blood donors [7.0 (4.1 to 9.9) years, both P’s< 0.001)], but also in HIV-positivecompared with HIV-negative participants (P < 0.001). Chronic HBV, higher anti-CMVIgG titer and CD8þ T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, ageadvancement was increased by 3.5 (0.1–6.8) years among those with nadir CD4þT-cell count less than 200 cells/ml and by 0.1 (0.06–0.2) years for each additionalmonth of exposure to saquinavir.

Journal article

Li L, Ribeiro Violante I, Leech R, Hampshire A, Opitz A, McArhur D, Carmichael D, Sharp Det al., 2019, Cognitive enhancement with Salience Network electrical stimulation is influenced by network structural connectivity, NeuroImage, Vol: 185, Pages: 425-433, ISSN: 1053-8119

The Salience Network (SN) and its interactions are important for cognitive control. We have previously shown that structural damage to the SN is associated with abnormal functional connectivity between the SN and Default Mode Network (DMN), abnormal DMN deactivation, and impaired response inhibition, which is an important aspect of cognitive control. This suggests that stimulating the SN might enhance cognitive control. Here, we tested whether non-invasive transcranial direct current stimulation (TDCS) could be used to modulate activity within the SN and enhance cognitive control. TDCS was applied to the right inferior frontal gyrus/anterior insula cortex during performance of the Stop Signal Task (SST) and concurrent functional (f)MRI. Anodal TDCS improved response inhibition. Furthermore, stratification of participants based on SN structural connectivity showed that it was an important influence on both behavioural and physiological responses to anodal TDCS. Participants with high fractional anisotropy within the SN showed improved SST performance and increased activation of the SN with anodal TDCS, whilst those with low fractional anisotropy within the SN did not. Cathodal stimulation of the SN produced activation of the right caudate, an effect which was not modulated by SN structural connectivity. Our results show that stimulation targeted to the SN can improve response inhibition, supporting the causal influence of this network on cognitive control and confirming it as a target to produce cognitive enhancement. Our results also highlight the importance of structural connectivity as a modulator of network to TDCS, which should guide the design and interpretation of future stimulation studies.

Journal article

Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil Set al., 2019, Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study, Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422

BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after

Journal article

Zetterberg H, Winblad B, Bernick C, Yaffe K, Majdan M, Johansson G, Newcombe V, Nyberg L, Sharp D, Tenovuo O, Blennow Ket al., 2018, Head trauma in sports - clinical characteristics, epidemiology and biomarkers., J Intern Med

Traumatic brain injury (TBI) is clinically divided into a spectrum of severities, with mild TBI being the least severe form and a frequent occurrence in contact sports, such as ice hockey, American football, rugby, horse riding and boxing. Mild TBI is caused by blunt nonpenetrating head trauma that causes movement of the brain and stretching and tearing of axons, with diffuse axonal injury being a central pathogenic mechanism. Mild TBI is in principle synonymous with concussion; both have similar criteria in which the most important elements are acute alteration or loss of consciousness and/or post-traumatic amnesia following head trauma and no apparent brain changes on standard neuroimaging. Symptoms in mild TBI are highly variable and there are no validated imaging or fluid biomarkers to determine whether or not a patient with a normal computerized tomography scan of the brain has neuronal damage. Mild TBI typically resolves within a few weeks but 10-15% of concussion patients develop postconcussive syndrome. Repetitive mild TBI, which is frequent in contact sports, is a risk factor for a complicated recovery process. This overview paper discusses the relationships between repetitive head impacts in contact sports, mild TBI and chronic neurological symptoms. What are these conditions, how common are they, how are they linked and can they be objectified using imaging or fluid-based biomarkers? It gives an update on the current state of research on these questions with a specific focus on clinical characteristics, epidemiology and biomarkers.

Journal article

Sridharan S, Raffel J, Nandoskar A, Record C, Brooks D, Owen D, Sharp D, Muraro P, Gunn R, Nicholas Ret al., 2018, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [F-18]GE-180: a blocking study using XDB173 in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 421-422, ISSN: 1352-4585

Conference paper

Underwood J, Cole JH, Leech R, Sharp DJ, Winston Aet al., 2018, Multivariate pattern analysis of volumetric neuroimaging data and its relationship with cognitive function in treated HIV-disease, Journal of Acquired Immune Deficiency Syndromes, Vol: 78, Pages: 429-436, ISSN: 1525-4135

BACKGROUND: Accurate prediction of longitudinal changes in cognitive function would potentially allow targeted intervention in those at greatest risk of cognitive decline. We sought to build a multivariate model using volumetric neuroimaging data alone to accurately predict cognitive function. METHODS: Volumetric T1-weighted neuroimaging data from virally suppressed HIV-positive individuals from the CHARTER cohort (n=139) were segmented into grey and white matter and spatially normalised before were entering into machine learning models. Prediction of cognitive function at baseline and longitudinally was determined using leave-one-out cross validation. Additionally, a multivariate model of brain ageing was used to measure the deviation of apparent brain age from chronological age and assess its relationship with cognitive function. RESULTS: Cognitive impairment, defined using the global deficit score, was present in 37.4%. However, it was generally mild and occurred more commonly in those with confounding comorbidities (p<0.001). Although multivariate prediction of cognitive impairment as a dichotomous variable at baseline was poor (AUC 0.59), prediction of the global T-score was better than a comparable linear model (adjusted R=0.08, p<0.01 vs. adjusted R=0.01, p=0.14). Accurate prediction of longitudinal changes in cognitive function was not possible (p=0.82).Brain-predicted age exceeded chronological age by mean (95% confidence interval) 1.17 (-0.14-2.53) years, but was greatest in those with confounding comorbidities (5.87 [1.74-9.99] years) and prior AIDS (3.03 [0.00-6.06] years). CONCLUSION: Accurate prediction of cognitive impairment using multivariate models using only T1-weighted data was not achievable, which may reflect the small sample size, heterogeneity of the data or that impairment was usually mild.

Journal article

Deb S, Leeson V, Aimola L, Bodani M, Li L, Weaver T, Sharp D, Crawford Met al., 2018, Aggression following traumatic brain injury: effectiveness of Risperidone (AFTER): study protocol for a feasibility randomised controlled trial, Trials, Vol: 19, ISSN: 1745-6215

BackgroundTraumatic brain injury (TBI) is a major public health concern and many people develop long-lasting physical and neuropsychiatric consequences following a TBI. Despite the emphasis on physical rehabilitation, it is the emotional and behavioural consequences that have greater impact on people with TBI and their families. One such problem behaviour is aggression which can be directed towards others, towards property or towards the self. Aggression is reported to be common after TBI (37–71%) and causes major stress for patients and their families. Both drug and non-drug interventions are used to manage this challenging behaviour, but the evidence-base for these interventions is poor and no drugs are currently licensed for the treatment of aggression following TBI. The most commonly used drugs for this purpose are antipsychotics, particularly second-generation drugs such as risperidone. Despite this widespread use, randomised controlled trials (RCTs) of antipsychotic drugs, including risperidone, have not been conducted. We have, therefore, set out to test the feasibility of conducting an RCT of this drug for people who have aggressive behaviour following TBI.Methods/designWe will examine the feasibility of conducting a placebo-controlled, double-blind RCT of risperidone for the management of aggression in adults with TBI and also assess participants’ views about their experience of taking part in the study.We will randomise 50 TBI patients from secondary care services in four centres in London and Kent to up to 4 mg of risperidone orally or an inert placebo and follow them up 12 weeks later. Participants will be randomised to active or control treatment in a 1:1 ratio via an external and remote web-based randomisation service. Participants will be assessed at baseline and 12-week follow-up using a battery of assessment scales to measure changes in aggressive behaviour (MOAS, IRQ) as well as global functioning (GOS-E, CGI), quality of life (EQ-5D-5L

Journal article

Cole JH, caan M, Underwood J, de Francesco D, van Zoest R, Wit F, Mutsaerts H, Leech R, Geurtsen G, Portigies P, Majoie C, Schim van der Loeff M, Sabin C, Reiss P, Winston A, Sharp Det al., 2018, No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project, Clinical Infectious Diseases, Vol: 66, Pages: 1899-1909, ISSN: 1058-4838

BackgroundDespite successful antiretroviral therapy people living with HIV (PLWH) experience higher rates of age-related morbidity, including abnormal brain structure, brain function and cognitive impairment. This has raised concerns that PLWH may experience accelerated ageing-related brain pathology.MethodsWe performed a multi-centre longitudinal study of 134 virologically-suppressed PLWH (median age = 56.0 years) and 79 demographically-similar HIV-negative controls (median age = 57.2 years). To measure cognitive performance and brain pathology, we conducted detailed neuropsychological assessments and multi-modality neuroimaging (T1-weighted, T2-weighted, diffusion-MRI, resting-state functional-MRI, spectroscopy, arterial spin labelling) at baseline and after two-year follow-up. Group differences in rates of change were assessed using linear mixed effects models.Results123 PLWH and 78 HIV-negative controls completed longitudinal assessments (median interval = 1.97 years). There were no differences between PLWH and HIV-negative controls in age, sex, years of education, smoking, alcohol use, recreational drug use, blood pressure, body-mass index or cholesterol levels.At baseline, PLWH had poorer global cognitive performance (P<0.01), lower grey matter volume (P=0.04), higher white matter hyperintensity load (P=0.02), abnormal white-matter microstructure (P<0.005) and greater ‘brain-predicted age difference’ (P=0.01). Longitudinally, there were no significant differences in rates of change in any neuroimaging measure between PLWH and HIV-negative controls (P>0.1). Cognitive performance was stable across the study period in both groups.ConclusionsOur finding indicate that when receiving successful treatment, middle-aged PLWH are not at increased risk of accelerated ageing-related brain changes or cognitive decline over two years, when compared to closely-matched HIV-negative controls.

Journal article

Whittington A, Sharp DJ, Gunn RN, 2018, Spatiotemporal distribution of β-amyloid in Alzheimer's disease results from heterogeneous regional carrying capacities, Journal of Nuclear Medicine, Vol: 59, Pages: 822-827, ISSN: 1535-5667

β-amyloid (Aβ) accumulation in the brain is one of two pathological hallmarks of Alzheimer's Disease (AD) and its spatial distribution has been studied extensively ex vivo. We apply mathematical modelling to Aβ in vivo PET imaging data in order to investigate competing theories of Aβ spread in AD. Our results provide evidence that Aβ accumulation starts in all brain regions simultaneously and that its spatiotemporal distribution is a result of heterogeneous regional carrying capacities (regional maximum possible concentration of Aβ) for the aggregated protein rather than longer term spreading from seed regions.

Journal article

Jenkins PO, De Simoni S, Bourke N, Fleminger J, Scott G, Towey D, Svensson W, Khan S, Patel M, Greenwood R, Cole J, Sharp DJet al., 2018, Dopaminergic abnormalities following traumatic brain injury, Brain, Vol: 141, Pages: 797-810, ISSN: 1460-2156

Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate–severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate–severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken toge

Journal article

Cole JH, Jolly A, De Simoni S, Bourke N, patel M, Scott G, Sharp Det al., 2018, Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury, Brain, Vol: 141, Pages: 822-836, ISSN: 1460-2156

Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of magnetic resonance imaging. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions, and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 moderate/severe traumatic brain injury patients (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (one-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterised using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarised regionally and compared with clinical and neuropsychological measures. Traumatic brain injury patients showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over one year was pronounced following traumatic brain injury. Traumatic brain injury patients lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates we

Journal article

Scott GPT, Zetterberg H, Jolly A, Cole JH, De Simoni S, Jenkins PO, Feeney C, Owen DR, Lingford-Hughes A, Howes O, Patel MC, Goldstone AP, Gunn RN, Blennow K, Matthews PM, Sharp DJet al., 2017, Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, Vol: 141, Pages: 459-471, ISSN: 1460-2156

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

Journal article

Li L, Violante I, Zimmerman K, Ross E, Leech R, Hampshire A, Carmichael D, Sharp Det al., 2017, EXPLORING THE TARGETED APPLICATION OF TDCS AFTER TBI, Publisher: BMJ PUBLISHING GROUP, Pages: A82-A82, ISSN: 0022-3050

Conference paper

Jenkins P, De Simoni S, Bourke N, Cole J, Sharp Det al., 2017, TARGETED TREATMENT FOR COGNITIVE IMPAIRMENTS FOLLOWING TRAUMATIC BRAIN INJURY WITH METHYLPHENIDATE, Publisher: BMJ PUBLISHING GROUP, Pages: A82-A82, ISSN: 0022-3050

Conference paper

De Simoni S, Jenkins PO, Bourke N, Fleminger JJ, Hellyer PJ, Jolly AE, Patel MC, Cole J, Leech R, Sharp DJet al., 2017, Altered caudate connectivity is associated with executive dysfunction after traumatic brain injury, Brain, Vol: 141, Pages: 148-164, ISSN: 1460-2156

Traumatic brain injury often produces executive dysfunction. This characteristic cognitive impairment often causes long-term problems with behaviour and personality. Frontal lobe injuries are associated with executive dysfunction, but it is unclear how these injuries relate to corticostriatal interactions that are known to play an important role in behavioural control. We hypothesized that executive dysfunction after traumatic brain injury would be associated with abnormal corticostriatal interactions, a question that has not previously been investigated. We used structural and functional MRI measures of connectivity to investigate this. Corticostriatal functional connectivity in healthy individuals was initially defined using a data-driven approach. A constrained independent component analysis approach was applied in 100 healthy adult dataset from the Human Connectome Project. Diffusion tractography was also performed to generate white matter tracts. The output of this analysis was used to compare corticostriatal functional connectivity and structural integrity between groups of 42 patients with traumatic brain injury and 21 age-matched controls. Subdivisions of the caudate and putamen had distinct patterns of functional connectivity. Traumatic brain injury patients showed disruption to functional connectivity between the caudate and a distributed set of cortical regions, including the anterior cingulate cortex. Cognitive impairments in the patients were mainly seen in processing speed and executive function, as well as increased levels of apathy and fatigue. Abnormalities of caudate functional connectivity correlated with these cognitive impairments, with reductions in right caudate connectivity associated with increased executive dysfunction, information processing speed and memory impairment. Structural connectivity, measured using diffusion tensor imaging between the caudate and anterior cingulate cortex was impaired and this also correlated with measures of ex

Journal article

Van Zoest RA, Underwood J, De Francesco D, Sabin CA, Cole JH, Wit FW, Caan MWA, Kootstra NA, Fuchs D, Zetterberg H, Majoie CBLM, Portegies P, Winston A, Sharp DJ, Gisslén M, Reiss P, Co-morBidity in Relation to AIDS COBRA Collaborationet al., 2017, Structural brain abnormalities in successfully treated HIV infection: associations with disease and cerebrospinal fluid biomarkers., Journal of Infectious Diseases, Vol: 217, Pages: 69-81, ISSN: 0022-1899

Background: Brain structural abnormalities have been reported in persons with HIV (PWH) on suppressive combination antiretroviral therapy (cART), but their pathophysiology remains unclear. Methods: We investigated factors associated with brain tissue volumes and white matter microstructure (fractional anisotropy) in 134 PWH on suppressive cART and 79 comparable HIV-negative controls, aged ≥45 years from the Co-morBidity in Relation to AIDS (COBRA) cohort, using multimodal neuroimaging and cerebrospinal fluid (CSF) biomarkers. Results: Compared to controls, PWH had lower grey matter volumes (-13.7 mL [95%-confidence interval -25.1, -2.2 mL]) and fractional anisotropy (-0.0073 [-0.012, -0.0024]), with the largest differences observed in those with prior clinical AIDS. Hypertension and CSF soluble CD14 concentration were associated with lower fractional anisotropy. These associations were independent of HIV serostatus (Pinteraction=0.32 and Pinteraction=0.59, respectively) and did not explain the greater abnormalities in brain structure in relation to HIV. Conclusions: The presence of lower grey matter volumes and more white matter microstructural abnormalities in well-treated PWH partly reflect a combination of historical effects of AIDS, as well as the more general influence of systemic factors such as hypertension and ongoing neuroinflammation. Additional mechanisms explaining the accentuation of brain structure abnormalities in treated HIV infection remain to be identified.

Journal article

Sharp D, 2017, Long-term inflammatory and neurodegenerative consequences of traumatic brain injury, 23rd World Congress of Neurology (WCN), Publisher: ELSEVIER SCIENCE BV, Pages: 11-11, ISSN: 0022-510X

Conference paper

Sharp D, 2017, Precision medicine in TBI: Lessons from dopaminergic treatment of cognitive impairment, 23rd World Congress of Neurology (WCN), Publisher: ELSEVIER SCIENCE BV, Pages: 1-2, ISSN: 0022-510X

Conference paper

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00306045&limit=30&person=true