Martin R Turner

University of Oxford, Oxford, England, United Kingdom

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Publications (84)446.11 Total impact

  • Martin R Turner, Kevin Talbot
    Clinical medicine (London, England) 08/2014; 14(4):456. · 1.32 Impact Factor
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    ABSTRACT: Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration.
    Brain : a journal of neurology. 06/2014;
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    ABSTRACT: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.
    Acta neuropathologica communications. 06/2014; 2(1):66.
  • Practical Neurology 05/2014;
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    ABSTRACT: ALS is a progressive neurodegenerative disease. The stage of disease reached can be described using a simple system based on the number of central nervous system regions involved. Historically, datasets have not attempted to record clinical stage, but being able to re-analyse the data by stage would have several advantages. We therefore explored the possibility of using an algorithm based on the revised ALS Functional Rating Scale (ALSFRS-R), which is commonly used in clinical practice, to estimate clinical stage. We devised an algorithm to convert ALSFRS-R score into clinical stage. ALSFRS-R domains were mapped to equivalent CNS regions. Stage 4 is reached when gastrostomy or non- invasive ventilation is needed, but as a proxy we used provision. We collected ALSFRS-R from clinic visits, and compared the estimation of clinical stage from the ALSFRS-R with the actual stage. Results showed that the agreement between staging by the two methods was excellent with an intraclass correlation coefficient of 0.92 (95% confidence interval 0.88-0.94). There was no systematic bias towards over-staging or under-staging using the algorithm. In conclusion, we have shown that clinical stage in ALS can be reliably estimated using the ALSFRS-R in historical data and in current data where stage has not been recorded.
    Amyotrophic lateral sclerosis & frontotemporal degeneration. 04/2014;
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease typically causing death within three years. Understanding the impact of disease on patients using health utility at different stages of ALS would allow meaningful cost-benefit analysis of new potential therapies. A common health-related quality of life measurement, developed and validated for the UK, is the EQ-5D. Using clinical trial data from the LiCALS study, we calculated health utility using the EQ-5D for each King's ALS clinical stage from 214 patients. We analysed whether health utility, and other health-related measures, significantly changed between each of the clinical stages. Results showed that mean health utility decreased by 0.487 (the scale runs from 1 to - 0.594) between clinical stages 2A and 4. Emotional states, measured using the Hospital Anxiety and Depression Scale (HADS), showed worsening depression and anxiety scores as ALS progressed. Age of onset, disease onset, gender and treatment group were not predictors of EQ-5D, depression or anxiety. In conclusion, increasing severity of King's ALS Clinical Stage is associated with a progressive decrease in EQ-5D health utility. This is useful for cost-benefit analysis of new therapies and validates this ALS clinical staging system.
    Amyotrophic lateral sclerosis & frontotemporal degeneration. 02/2014;
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    ABSTRACT: Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1)(G93A) transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T2-weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural (T2, T1, apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T2-weighted images from as early as 60 days (P<0.05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T2-weighted changes. Significant reductions in ADC (P<0.01) and MTR (P<0.05) were found at 120 days in the same brainstem nuclei. No changes in T1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T2-weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents.Journal of Cerebral Blood Flow & Metabolism advance online publication, 5 February 2014; doi:10.1038/jcbfm.2014.19.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2014; · 5.46 Impact Factor
  • Dirk Bäumer, Kevin Talbot, Martin R Turner
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    ABSTRACT: Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.
    Journal of the Royal Society of Medicine 01/2014; 107(1):14-21. · 1.72 Impact Factor
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons. Advanced MRI techniques such as diffusion tensor imaging have shown great potential in capturing a common white matter pathology. However the sensitivity is variable and diffusion tensor imaging is not yet applicable to the routine clinical environment. Voxel-based morphometry (VBM) has revealed grey matter changes in ALS, but the bias-reducing algorithms inherent to traditional VBM are not optimized for the assessment of the white matter changes. We have developed a novel approach to white matter analysis, namely voxel-based intensitometry (VBI). High resolution T1-weighted MRI was acquired at 1.5 Tesla in 30 ALS patients and 37 age-matched healthy controls. VBI analysis at the group level revealed widespread white matter intensity increases in the corticospinal tracts, corpus callosum, sub-central, frontal and occipital white matter tracts and cerebellum. VBI results correlated with disease severity (ALSFRS-R) and patterns of cerebral involvement differed between bulbar- and limb-onset. VBI would be easily translatable to the routine clinical environment, and once optimized for individual analysis offers significant biomarker potential in ALS.
    PLoS ONE 01/2014; 9(8):e104894. · 3.73 Impact Factor
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    ABSTRACT: The onset of motor symptoms in amyotrophic lateral sclerosis (ALS) is strikingly focal. In three-quarters of cases, weakness emerges unilaterally in one limb, typically spreading contiguously over months to become bilateral.(1) An extremely rare clinical syndrome of upper motor neuron-predominant, progressive hemiparesis was first described by American neurologist Charles Karsner Mills (1845-1930).(2) More typical ALS shares a common histopathologic signature with frontotemporal dementia (FTD), consisting of ubiquitinated neuronal and glial inclusions containing the DNA and RNA binding protein, TDP-43. Cognitive impairment may be detected in at least one-third of ALS cases and involves mainly deficits in language, executive function, and fluency, with variable levels of behavioral impairments that all have overlap with the purer FTD syndromes. Frank FTD is seen in up to 15% of patients with ALS, in whom it typically occurs before or soon after the development of motor symptoms, and is associated with a more rapid disease progression.(3.)
    Neurology 12/2013; · 8.25 Impact Factor
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    Andrew Eisen, Martin R Turner, Roger Lemon
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    ABSTRACT: We propose that amyotrophic lateral sclerosis (ALS), and frontotemporal dementia may be viewed as a failure of interlinked functional complexes having their origins in key evolutionary adaptations. We discuss how hand-arm function, locomotion, brain-stem function (involving vocalization/speech, swallowing and breathing), and cognitive impairment share complex, inter-dependent evolutionary adaptations that can be traced back several million years. Fine movements of the hand facilitated tool-making and use enhanced by development of bipedalism. Development of the larynx and integration of respiratory control were central to vocalization, which when combined with gesture are intermediary to human language. These adaptations were accompanied by progressive encephalization, with development of Theory of Mind to facilitate socialization. The varied clinical phenotypes of ALS can thus be understood in the context of inter-related functional complexes that subserve "Tools and Talk"; they have a long evolutionary history and are related to specific developmental neural and gene networks. © 2013 Wiley Periodicals, Inc.
    Muscle & Nerve 11/2013; · 2.31 Impact Factor
  • Martin R Turner
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    ABSTRACT: Neurophysiology studies in a 50-year-old man with slowly progressive weakness of the left upper limb revealed conduction block in the ulnar nerve above the elbow. His weakness remained stable with regular subcutaneous immunoglobulin, but he noted gradual hemibody hair depigmentation. Examination also revealed unilateral left hand leukonychia (figure). MRI of the brain and cervical spine was normal.
    Neurology 11/2013; 81(20):1800-1. · 8.25 Impact Factor
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    ABSTRACT: Studies have produced contradictory evidence for seasonal variation in the incidence of Guillain-Barre Syndrome (GBS), possibly due to the potentially confounding factor of the prodromal illness, for example peaks in Winter following influenza balanced by peaks in Summer due to diarrhoeal disease. The morbidity and mortality of GBS is influenced by the subtype of neuronal pathology, which may also depend upon the nature of the prodromal illness, for example axonal forms being associated with Campylobacter jejuni infection. In an attempt to study these interactions, we performed a retrospective cohort study of admission for GBS at a large teaching hospital to identify seasonal variation in incidence, subtype and associated prodromal illness. Patients admitted to the Oxford University Hospitals NHS Trust from 2001-2012 were initially identified as having a primary diagnosis of GBS by hospital coding. Seasons were defined as 3 month periods, starting from January to March (Winter). Clinical notes were then reviewed to confirm the diagnosis. Where available, the neurophysiological subtype and nature of any prodromal illness were identified. Variation in seasonal incidence was determined by chi-squared tests, and continuous variables were compared using ANOVA. Over the 11 year period, 140 patients were confirmed as having GBS, comprising 111 AIDP, 10 AMAN, 6 ASMAN, 5 Miller Fisher, 8 undetermined. There was a significant variation in seasonal incidence (p=0.037), with GBS significantly more common in Winter versus Summer (48 versus 25, p=0.007), with comparable numbers in Autumn (33) and Spring (34). A shorter average length of stay was observed in Winter compared to other seasons (15 versus 25 days, p=0.02). A specific entry regarding prodromal illness was identifiable in the clinical notes of 59/140 (42%). Of these, 22 (37%) reported an influenza-like illness, and 19 (32%) a diarrhoeal illness. In these cases, the increased incidence of GBS in Winter was partly explained by an increased incidence of GBS preceded by an influenza-like illness in Winter versus Summer (14 versus 3, p=0.012). Although there was no significant relationship between prodromal illness and GBS subtype due to the low number of axonal forms, where identifiable, all cases of AMAN had a diarrhoeal prodromal illness. In this study population, we demonstrated a significant Winter peak of GBS admissions, which we interpret as being related to the increased incidence of influenza-like illnesses. Possible factors in the significantly shorter hospital stay we observed during these peak times include less severe cases, or the increased preparedness of acute services.
    Journal of neurology, neurosurgery, and psychiatry 11/2013; 84(11):e2. · 4.87 Impact Factor
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    ABSTRACT: There have been a large number of case-control studies using diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS). The objective of this study was to perform an individual patient data (IPD) meta-analysis for the estimation of the diagnostic accuracy measures of DTI in the diagnosis of ALS using corticospinal tract data. MEDLINE, EMBASE, CINAHL, and Cochrane databases (1966-April 2011) were searched. Studies were included if they used DTI region of interest or tractography techniques to compare mean cerebral corticospinal tract fractional anisotropy values between ALS subjects and healthy controls. Corresponding authors from the identified articles were contacted to collect individual patient data. IPD meta-analysis and meta-regression were performed using Stata. Meta-regression covariate analysis included age, gender, disease duration, and Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores. Of 30 identified studies, 11 corresponding authors provided IPD and 221 ALS patients and 187 healthy control subjects were available for study. Pooled area under the receiver operating characteristic curve (AUC) was 0.75 (95% CI: 0.66-0.83), pooled sensitivity was 0.68 (95% CI: 0.62-0.75), and pooled specificity was 0.73 (95% CI: 0.66-0.80). Meta-regression showed no significant differences in pooled AUC for each of the covariates. There was moderate to high heterogeneity of pooled AUC estimates. Study quality was generally high. Data from 19 of the 30 eligible studies were not ascertained, raising possibility of selection bias. Using corticospinal tract individual patient data, the diagnostic accuracy of DTI appears to lack sufficient discrimination in isolation. Additional research efforts and a multimodal approach that also includes ALS mimics will be required to make neuroimaging a critical component in the workup of ALS.
    Academic radiology 09/2013; 20(9):1099-106. · 2.09 Impact Factor
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    ABSTRACT: To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease. An all-England hospital record-linkage dataset spanning 1999-2011 was used. Cohorts were constructed of people with each of a range of autoimmune diseases; the incidence of ALS in each disease cohort was compared with the incidence of ALS in a cohort of individuals without prior admission for the autoimmune disease. There were significantly more cases than expected of ALS associated with a prior diagnosis of asthma, celiac disease, younger-onset diabetes (younger than 30 years), multiple sclerosis, myasthenia gravis, myxedema, polymyositis, Sjögren syndrome, systemic lupus erythematosus, and ulcerative colitis. Autoimmune disease associations with ALS raise the possibility of shared genetic or environmental risk factors.
    Neurology 08/2013; · 8.25 Impact Factor
  • Andrew Eisen, Martin R Turner
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    ABSTRACT: Alzheimer's disease (AD) is 10-fold more frequent than Parkinson's disease (PD), which in turn is 10-fold more frequent than amyotrophic lateral sclerosis (ALS). The differences between these neurodegenerative diseases have been ascribed to a selective vulnerability of specific neuronal sub-types that then determine each disorder. However, there are non-neuronal cells that are ubiquitously and possibly primarily involved in all of them, and they share regulatory mechanisms through similar interneurons and, typically inhibitory, neurotransmitters. There is recognized clinical and neuropathological overlap between AD, PD and ALS, the best example being Guamanian Lytico-Bodig, but increasingly recognized in larger populations, e.g. carriers of C9orf72 hexanucleotide expansions. From early embryogenesis to adulthood, genetic and experience-dependent functional neural networks develop primarily in relation to the neocortex. From an evolutionary standpoint, cognition, memory, executive function, linguistics and fine motor function are most prominent in humans. It is concluded that neural networks, rather than specific neuronal sub-types defined regionally or by individual transmitters, underlie the marked differences between neurodegenerative disorders in terms of susceptibility and clinical features. This requires the continued development of strategies to study brain function in health and disease as the 'system', greater than the sum of its parts.
    Amyotrophic lateral sclerosis & frontotemporal degeneration. 07/2013;
  • Practical Neurology 07/2013;
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    Hiroshi Mitsumoto, Martin R. Turner
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 05/2013; 14(S1). · 2.37 Impact Factor
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    ABSTRACT: To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference.
    Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 05/2013; 14(S1). · 2.37 Impact Factor
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    ABSTRACT: Primary lateral sclerosis (PLS) has been regarded as a rare, extreme form of amyotrophic lateral sclerosis (ALS). Like ALS, it is a clinical diagnosis without established biomarkers. We sought to explore loss of cerebral myelin in relation to clinical features, including cognitive impairment, in cases of both ALS and PLS. A novel MRI sequence (mcDESPOT) sensitive to water pools within myelin and intra- and extra-cellular spaces was applied to 23 ALS patients, seven PLS patients and 12 healthy controls, with interval follow-up in 15 ALS and four PLS patients. Results demonstrated that PLS patients were distinguished by widespread cerebral myelin water fraction reductions, independent of disease duration and clinical upper motor neuron burden. ALS patients showed a significant increase in intra- and extra-cellular water, indirectly linked to neuroinflammatory activity. Limited measures of cognitive impairment in the ALS group were associated with myelin changes within the anterior corpus callosum and frontal lobe projections. Longitudinal changes were only significant in the PLS group. In conclusion, in this exploratory study, myelin imaging has potential to distinguish PLS from ALS, and may have value as a marker of extramotor involvement. PLS may be a more active cerebral pathological process than its rate of clinical deterioration suggests.
    Amyotrophic lateral sclerosis & frontotemporal degeneration. 05/2013;

Publication Stats

1k Citations
446.11 Total Impact Points

Institutions

  • 2009–2014
    • University of Oxford
      • • Nuffield Department of Clinical Neurosciences
      • • Department of Public Health
      Oxford, England, United Kingdom
    • Nottingham University Hospitals NHS Trust
      Nottigham, England, United Kingdom
  • 2007–2014
    • Oxford University Hospitals NHS Trust
      • • Department of Clinical Neurology
      • • Department of Neurology
      Oxford, England, United Kingdom
  • 2013
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 2007–2012
    • King's College London
      • MRC Centre for Neurodegeneration Research
      London, ENG, United Kingdom