Imperial College London

DrNeilGraham

Faculty of MedicineDepartment of Brain Sciences

Clinical Lecturer
 
 
 
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neil.graham

 
 
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Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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13 results found

Graham NSN, Zimmerman KA, Moro F, Heslegrave A, Maillard SA, Bernini A, Miroz J-P, Donat CK, Lopez MY, Bourke N, Jolly AE, Mallas E-J, Soreq E, Wilson MH, Fatania G, Roi D, Patel MC, Garbero E, Nattino G, Baciu C, Fainardi E, Chieregato A, Gradisek P, Magnoni S, Oddo M, Zetterberg H, Bertolini G, Sharp DJet al., 2021, Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury, Science Translational Medicine, Vol: 13, Pages: 1-15, ISSN: 1946-6234

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

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

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

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

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

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

Graham N, Junghans C, Downes R, Sendall C, Lai H, McKirdy A, Elliott P, Howard R, Wingfield D, Priestman M, Ciechonska M, Cameron L, Storch M, Crone MA, Freemont PS, Randell P, McLaren R, Lang N, Ladhani S, Sanderson F, Sharp DJet al., 2020, SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes, Journal of Infection, Vol: 81, Pages: 411-419, ISSN: 0163-4453

OBJECTIVES: To understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents. METHODS: An outbreak investigation involving 394 residents and 70 staff, was carried out in 4 nursing homes affected by COVID-19 outbreaks in central London. Two point-prevalence surveys were performed one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing. RESULTS: Overall, 26% (95% CI 22 to 31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70 to 336) compared with previous years. Systematic testing identified 40% (95% CI 35 to 46) of residents as positive for SARS-CoV-2, and of these 43% (95% CI 34 to 52) were asymptomatic and 18% (95% CI 11 to 24) had only atypical symptoms; 4% (95% CI -1 to 9) of asymptomatic staff also tested positive. CONCLUSIONS: The SARS-CoV-2 outbreak in four UK nursing homes was associated with very high infection and mortality rates. Many residents developed either atypical or no discernible symptoms. A number of asymptomatic staff members also tested positive, suggesting a role for regular screening of both residents and staff in mitigating future outbreaks.

Journal article

Graham NSN, Junghans C, Downes R, Sendall C, Lai H, McKirdy A, Elliott P, Howard R, Wingfield D, Priestman M, Ciechonska M, Cameron L, Storch M, Crone MA, Freemont PS, Randell P, McLaren R, Lang N, Ladhani S, Sanderson F, Sharp DJet al., 2020, SARS-CoV-2 infection, clinical features and outcome of COVID-19 in United Kingdom nursing homes, Publisher: Cold Spring Harbor Laboratory

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>To understand SARS-Co-V-2 infection and transmission in UK nursing homes in order to develop preventive strategies for protecting the frail elderly residents.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>An outbreak investigation.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>4 nursing homes affected by COVID-19 outbreaks in central London.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>394 residents and 70 staff in nursing homes.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Two point-prevalence surveys one week apart where residents underwent SARS-CoV-2 testing and had relevant symptoms documented. Asymptomatic staff from three of the four homes were also offered SARS-CoV-2 testing.</jats:p></jats:sec><jats:sec><jats:title>Main outcome measures</jats:title><jats:p>All-cause mortality, and mortality attributed to COVID-19 on death certificates. Prevalence of SARS-CoV-2 infection and symptoms in residents and staff.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Overall, 26% (95% confidence interval 22 to 31) of residents died over the two-month period. All-cause mortality increased by 203% (95% CI 70 to 336). Systematic testing identified 40% (95% CI 35 to 46) of residents, of whom 43% (95% CI 34 to 52) were asymptomatic and 18% (95% CI 11 to 24) had atypical symptoms, as well as 4% (95% CI -1 to 9) of asymptomatic staff who tested positive for SARS-CoV-2.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The SARS-CoV-2 outbreak was associated with a ver

Working paper

Graham NSN, Sharp DJ, 2019, Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia, Journal of Neurology, Neurosurgery & Psychiatry, Vol: 90, ISSN: 0022-3050

Traumatic brain injury (TBI) leads to increased rates of dementia, including Alzheimer’s disease. The mechanisms by which trauma can trigger neurodegeneration are increasingly understood. For example, diffuse axonal injury is implicated in disrupting microtubule function, providing the potential context for pathologies of tau and amyloid to develop. The neuropathology of post-traumatic dementias is increasingly well characterised, with recent work focusing on chronic traumatic encephalopathy (CTE). However, clinical diagnosis of post-traumatic dementia is problematic. It is often difficult to disentangle the direct effects of TBI from those produced by progressive neurodegeneration or other post-traumatic sequelae such as psychiatric impairment. CTE can only be confidently identified at postmortem and patients are often confused and anxious about the most likely cause of their post-traumatic problems. A new approach to the assessment of the long-term effects of TBI is needed. Accurate methods are available for the investigation of other neurodegenerative conditions. These should be systematically employed in TBI. MRI and positron emission tomography neuroimaging provide biomarkers of neurodegeneration which may be of particular use in the postinjury setting. Brain atrophy is a key measure of disease progression and can be used to accurately quantify neuronal loss. Fluid biomarkers such as neurofilament light can complement neuroimaging, representing sensitive potential methods to track neurodegenerative processes that develop after TBI. These biomarkers could characterise endophenotypes associated with distinct types of post-traumatic neurodegeneration. In addition, they might profitably be used in clinical trials of neuroprotective and disease-modifying treatments, improving trial design by providing precise and sensitive measures of neuronal loss.

Journal article

Graham NSN, Holmes PA, Rudd AG, 2015, Post-stroke Seizures, Management of Post-Stroke Complications, Publisher: Springer, Pages: 33-50, ISBN: 9783319178554

This book highlights the underlying importance of post-stroke complications during recovery, allowing healthcare professionals managing stroke patients to understand their frequency and identify which patients are at risk of developing such ...

Book chapter

Graham N, Rashiq H, Hunt BJ, 2014, Testing for thrombophilia: clinical update, BRITISH JOURNAL OF GENERAL PRACTICE, Vol: 64, Pages: E120-E122, ISSN: 0960-1643

Journal article

Graham NSN, Crichton S, Koutroumanidis M, Wolfe CDA, Rudd AGet al., 2013, Incidence and Associations of Poststroke Epilepsy, Stroke, Vol: 44, Pages: 605-611, ISSN: 0039-2499

<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>To describe the epidemiology and associations of poststroke epilepsy (PSE) because there is limited evidence to inform clinicians and guide future research.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>Data were collected from the population-based South London Stroke Register of first strokes in a multiethnic inner-city population with a maximum follow-up of 12 years. Self-completed forms and interviews notified study organizers of epilepsy diagnosis. Kaplan–Meier methods and Cox models were used to assess associations with sociodemographic factors, clinical features, stroke subtype, and severity markers.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> Three thousand three-hundred ten patients with no history of epilepsy presented with first stroke between 1995 and 2007, with a mean follow-up of 3.8 years. Two-hundred thirteen subjects (6.4%) had development of PSE. PSE incidence at 3 months and 1, 5, and 10 years were estimated at 1.5%, 3.5%, 9.0%, and 12.4%, respectively. Sex, ethnicity, and socioeconomic status were not associations, but markers of cortical location, including dysphasia, visual neglect, and field defect, along with stroke severity indices at presentation, including low Glasgow Coma Scale, incontinence, or poor function on Barthel Index, were associated with PSE on univariate analysis. Young age was independently associated with PSE, affecting 10.7% of patients aged &lt;65 years and 1.6% &gt;85 years ( <jats:italic>P</jats:italic> ≤0.001) on 10-year estimates. Independent predictors of PSE also included visual neglect, dysphasia, and stroke subtyp

Journal article

Graham NSN, Birns J, Dargan PI, Wood DM, Bhalla Aet al., 2012, Gamma-hydroxybutyrate toxicity mimicking basilar artery stroke, British Journal of Hospital Medicine, Vol: 73, Pages: 412-413, ISSN: 1750-8460

Journal article

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