Martin R Turner

University of Oxford, Oxford, England, United Kingdom

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Publications (111)565.65 Total impact

  • Martin R Turner · Elizabeth Gray
    Journal of Neurology Neurosurgery & Psychiatry 10/2015; DOI:10.1136/jnnp-2015-311934 · 6.81 Impact Factor
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    ABSTRACT: Advanced magnetic resonance imaging (MRI) techniques hold the promise to capture upper motor neuron loss and extramotor brain changes in amyotrophic lateral sclerosis (ALS) and as such deliver biomarkers relevant to diagnosis, prognosis and monitoring disease progression. However, a correlation between imaging parameters and clinical metrics has thus far been inconsistent across studies. We discuss the contributing factors to this clinical-imaging correlation gap as well as its implications for future research.
    09/2015; DOI:10.3109/21678421.2015.1051989
  • Martin R Turner · Raph Goldacre · Kevin Talbot · Michael J Goldacre
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    ABSTRACT: To use an unbiased method to test a previously reported association between cerebral arteriovenous malformation (AVM) embolisation and the subsequent development of amyotrophic lateral sclerosis (ALS). A hospital record linkage database was used to create cohorts of individuals coded as having cerebral and peripheral vessel AVMs, stroke (separately for haemorrhagic and ischaemic), transient ischaemic attack (TIA) and subarachnoid haemorrhage (SAH). The rate ratio for subsequent ALS was compared to a reference cohort. An increased rate ratio for ALS was found in relation to prior AVM (2.69; p=0.005), all strokes (1.38; p<0.001), and TIA (1.47; p<0.001). Cerebrovascular injury from a variety of causes, rather than the presence of AVM or the associated embolisation procedure per se, may be a risk factor for ALS within the context of a more complex multiple-hit model of pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of neurology, neurosurgery, and psychiatry 08/2015; DOI:10.1136/jnnp-2015-311157 · 6.81 Impact Factor
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    ABSTRACT: A relative preservation of eye movements is notable in ALS, but saccadic functions have not been studied longitudinally. ALS overlaps with FTD, typically involving executive dysfunction, and eye-tracking offers additional potential for the assessment of extramotor pathology where writing and speaking are both impaired. Eye-tracking measures (including anti-saccade, trail-making and visual search tasks) were assessed at six-monthly intervals for up to two years in a group of ALS (n = 61) and primary lateral sclerosis (n = 7) patients, compared to healthy age-matched controls (n = 39) assessed on a single occasion. Task performance was explored speculatively in relation to resting-state functional MRI (R-FMRI) network connectivity. Results showed that ALS patients were impaired on executive and visual search tasks despite normal basic saccadic function, and impairments in the PLS patients were unexpectedly often more severe. No significant progression was detected longitudinally in either group. No changes in R-FMRI network connectivity were identified in relation to patient performance. In conclusion, eye-tracking offers an objective means to assess extramotor cerebral involvement in ALS. The relative resistance of pure oculomotor function is confirmed, and higher-level executive impairments do not follow the same rate of decline as physical disability. PLS patients may have more cortical dysfunction than has been previously appreciated.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 07/2015; DOI:10.3109/21678421.2015.1054292 · 2.41 Impact Factor
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    Martin R Turner · Esther Verstraete
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.
    Current Neurology and Neuroscience Reports 07/2015; 15(7):569. DOI:10.1007/s11910-015-0569-6 · 3.06 Impact Factor
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    ABSTRACT: Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance (1H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The 1H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (n = 41) for up to two years, and in healthy controls at a single time-point (n = 14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that 1H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 06/2015; DOI:10.3109/21678421.2015.1053490 · 2.41 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 06/2015; DOI:10.3109/21678421.2015.1051987 · 2.41 Impact Factor
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    ABSTRACT: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls. © 2015 American Academy of Neurology.
    Neurology 05/2015; 84(22). DOI:10.1212/WNL.0000000000001642 · 8.29 Impact Factor
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    ABSTRACT: Objective Diffusion tensor imaging (DTI) is sensitive to white matter tract pathology. A core signature involving the corticospinal tracts (CSTs) has been identified in amyotrophic lateral sclerosis (ALS). Raised neurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) is thought to reflect axonal damage in a range of neurological disorders. The relationship between these two measures was explored.MethodsCSF and serum NfL concentrations and DTI acquired at 3 Tesla on the same day were obtained from ALS patients (n = 25 CSF, 40 serum) and healthy, age-similar controls (n = 17 CSF, 25 serum). Within-group correlations between NfL and DTI measures of microstructural integrity in major white matter tracts (CSTs, superior longitudinal fasciculi [SLF], and corpus callosum) were performed using tract-based spatial statistics.ResultsNfL levels were higher in patients compared to controls. CSF levels correlated with clinical upper motor neuron burden and rate of disease progression. Higher NfL levels were significantly associated with lower DTI fractional anisotropy and increased radial diffusivity in the CSTs of ALS patients, but not in controls.InterpretationElevated CSF and serum NfL is, in part, a result of CST degeneration in ALS. This highlights the wider potential for combining neurochemical and neuroimaging-based biomarkers in neurological disease.
    05/2015; 2(7). DOI:10.1002/acn3.212
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    ABSTRACT: There is growing evidence that mirror neurons, initially discovered over two decades ago in the monkey, are present in the human brain. In the monkey, mirror neurons characteristically fire not only when it is performing an action, such as grasping an object, but also when observing a similar action performed by another agent (human or monkey). In this review we discuss the origin, cortical distribution and possible functions of mirror neurons as a background to exploring their potential relevance in amyotrophic lateral sclerosis (ALS). We have recently proposed that ALS (and the related condition of frontotemporal dementia) may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. This can include loss of the direct projections from the corticospinal tract, and this is at least part of the explanation for impaired motor control in ALS. Since, in the monkey, corticospinal neurons also show mirror properties, ALS in humans might also affect the mirror neuron system. We speculate that a defective mirror neuron system might contribute to other ALS deficits affecting motor imagery, gesture, language and empathy. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 02/2015; 126(7). DOI:10.1016/j.clinph.2015.02.003 · 3.10 Impact Factor
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    Martin R Turner · Michael Swash
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    ABSTRACT: Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Neurology Neurosurgery & Psychiatry 02/2015; 86(6). DOI:10.1136/jnnp-2014-308946 · 6.81 Impact Factor
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    ABSTRACT: Objective Whether circulating microvesicles convey bioactive signals in neurodegenerative diseases remains currently unknown. In this study, we investigated the biochemical composition and biological function of exosomes isolated from sera of patients with Parkinson's disease (PD).Methods Proteomic analysis was performed on microvesicle preparations from grouped samples of patients with genetic and sporadic forms of PD, amyotrophic lateral sclerosis, and healthy subjects. Nanoparticle-tracking analysis was used to assess the number and size of exosomes between patient groups. To interrogate their biological effect, microvesicles were added to primary rat cortical neurons subjected to either nutrient deprivation or sodium arsenite.ResultsAmong 1033 proteins identified, 23 exosome-associated proteins were differentially abundant in PD, including the regulator of exosome biogenesis syntenin 1. These protein changes were detected despite similar exosome numbers across groups suggesting that they may reflect exosome subpopulations with distinct functions. Accordingly, we showed in models of neuronal stress that Parkinson's-derived microvesicles have a protective effect.InterpretationCollectively, these data suggest for the first time that immunophenotyping of circulating exosome subpopulations in PD may lead to a better understanding of the systemic response to neurodegeneration and the development of novel therapeutics.
    02/2015; 2(a):353. DOI:10.1002/acn3.175
  • Martin R Turner · Matthew C Kiernan
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    ABSTRACT: Once a patient has been diagnosed with the neurodegenerative disorder amyotrophic lateral sclerosis (ALS),1 management varies considerably around the world. Some patients are managed by a variety of healthcare professionals, for example, a primary care physician, a neurologist, general or palliative care physician, who may each act in relative isolation. Alternatively, it may involve more recently developed multidisciplinary models of care, led by someone with specialised knowledge of the uniquely complex, often rapidly-evolving needs of this patient group, and of those that care for them. The Motor Neurone Disease Association of England, Wales and Northern Ireland, established in 1979, pioneered a Care Centre model of ALS led by a coordinator, typically with a nursing background. It seems logical that the concentration of patients with ALS in highly specialised clinics would go hand in hand with the accumulation of resources and clinical expertise, … [Full text of this article]
    Journal of Neurology Neurosurgery & Psychiatry 12/2014; 86(5). DOI:10.1136/jnnp-2014-309829 · 6.81 Impact Factor
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    ABSTRACT: Evidence for seasonal variation in incidence and subtype of Guillain-Barré syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis. We searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001-2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype. Across 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02-1.27, p=0.020), with significant heterogeneity between studies (I(2)=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18-3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84-5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60-2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75). Incidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Neurology Neurosurgery & Psychiatry 12/2014; DOI:10.1136/jnnp-2014-309056 · 6.81 Impact Factor
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    ABSTRACT: Objectives The use of clinical staging in the fatal neurodegenerative disease amyotrophic lateral sclerosis would have value in optimising future therapeutic trials. We aimed to use previous clinical trial data to determine the length of time patients spend in each of four proposed stages, its range and transition patterns to subsequent stages. Methods Using databases from two multicentre clinical trials, patients were retrospectively staged through the trial course. At each stage we assessed whether patients then progressed to an earlier, consecutive or later stage or death. Duration spent in each stage before progression to a later stage was calculated. Results There were 725 patients. No patients moved to an earlier stage. More patients at stages 1, 2 and 3 progressed to the consecutive stage rather than skipping a stage. 59.3% of patients at Stage 1 progressed to Stage 2, 54.0% of patients at Stage 2 progressed to Stage 3, 42.3% of patients at Stage 3 progressed to Stage 4 and 47.0% of Stage 4 patients progressed to death. Transition times between stages had a median duration of 3 to 7 months for stages 2 to 4. Discussion We have shown using trial data that transition times between stages are short. Use of stage duration as an endpoint might allow a shorter trial duration. We have shown face validity in this system as most patients progress through consecutive stages, and none revert to earlier stages. Furthermore, we have shown the system is reliable across populations and therefore has content validity.
    Journal of neurology, neurosurgery, and psychiatry 12/2014; 86(1). DOI:10.1136/jnnp-2013-306865 · 6.81 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This Review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. ANN NEUROL 2014. © 2014 American Neurological Association
    Annals of Neurology 11/2014; 76(5). DOI:10.1002/ana.24273 · 9.98 Impact Factor
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    Martin R. Turner · Michael Benatar
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    ABSTRACT: Multiple candidate biomarkers for amyotrophic lateral sclerosis (ALS) have emerged across a range of platforms. Replication of results, however, has been absent in all but a few cases, and the range of control samples has been limited. If progress towards clinical translation is to continue, the specific biomarker needs of ALS, which differ from those of other neurodegenerative disorders, as well as the challenges inherent to longitudinal ALS biomarker cohorts, must be understood. Appropriate application of multimodal approaches, international collaboration, pre-symptomatic studies, and biomarker integration into future therapeutic trials are among the essential priorities going forward. © 2014 Wiley Periodicals, Inc.
    Muscle & Nerve 11/2014; 51(1). DOI:10.1002/mus.24470 · 2.28 Impact Factor
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    ABSTRACT: Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
    Neuron 10/2014; 84(2):324-31. DOI:10.1016/j.neuron.2014.09.027 · 15.05 Impact Factor
  • Practical Neurology 09/2014; 15(1). DOI:10.1136/practneurol-2014-000950
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    ABSTRACT: Objective: We tested whether it is possible to differentiate relapsing-remitting (RR) from secondary progressive (SP) disease stages in patients with multiple sclerosis (MS) using a combination of nuclear magnetic resonance (NMR) metabolomics and partial least squares discriminant analysis (PLS-DA) of biofluids, which makes no assumptions on the underlying mechanisms of disease.Methods: Serum samples were obtained from patients with primary progressive MS (PPMS), SPMS, and RRMS; patients with other neurodegenerative conditions; and age-matched controls. Samples were analyzed by NMR and PLS-DA models were derived to separate disease groups.Results: The PLS-DA models for serum samples from patients with MS enabled reliable differentiation between RRMS and SPMS. This approach also identified significant differences between the metabolite profiles of each of the MS groups (PP, SP, and RR) and the healthy controls, as well as predicting disease group membership with high specificity and sensitivity.Conclusions: NMR metabolomics analysis of serum is a sensitive and robust method for differentiating between different stages of MS, yielding diagnostic markers without a priori knowledge of disease pathogenesis. Critically, this study identified and validated a type II biomarker for the RR to SP transition in patients with MS. This approach may be of considerable benefit in categorizing patients for treatment and as an outcome measure in future clinical trials.Classification of evidence: This study provides Class II evidence that serum metabolite profiles accurately distinguish patients with different subtypes and stages of MS.
    Neurology 09/2014; 83(17). DOI:10.1212/wnl.0000000000000905 · 8.29 Impact Factor

Publication Stats

2k Citations
565.65 Total Impact Points


  • 2009–2015
    • University of Oxford
      • Nuffield Department of Clinical Neurosciences
      Oxford, England, United Kingdom
  • 2008–2014
    • Oxford University Hospitals NHS Trust
      • • Department of Clinical Neurology
      • • Department of Neurology
      Oxford, England, United Kingdom
  • 2012
    • Royal Berkshire NHS Foundation Trust
      Reading, England, United Kingdom
  • 2003–2008
    • King's College London
      • • Institute of Psychiatry
      • • MRC Centre for Neurodegeneration Research
      Londinium, England, United Kingdom