Scholarly Works - Clinical Neurosciences
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Item Open Access Accepted version Peer-reviewed Is there a role for postoperative physiotherapy in degenerative cervical myelopathy? A systematic review.(SAGE, 2018-09-01) Badran, Abdul; Davies, Benjamin M; Bailey, Heidi-Marie; Kalsi-Ryan, Sukhvinder; Kotter, Mark Rn; Davies, Ben [0000-0003-0591-5069]; Kotter, Mark [0000-0001-5145-7199]OBJECTIVE: To review peer-reviewed literature relating to postoperative physiotherapy for degenerative cervical myelopathy (DCM), to determine efficacy in improving clinical outcome and recovery. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, PEDro, ISRCTN registry, WHO ICTRP and Clinicaltrials.gov . References and citations of relevant articles were searched. METHODS: A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42016039511) from the origins of the databases till 15 February 2018. Included were all studies investigating physiotherapy as an intervention after surgical treatment of DCM to determine effect on clinical outcome and recovery. Study quality was determined using the Grades of Recommendation, Assessment, Development and Evaluation guidelines. RESULTS: In all, 300 records were identified through tailored systematic searches, after removing duplicates. After screening, only one investigated postoperative rehabilitation using physiotherapy for DCM; however, this was retrospective with no controls. This study suggested that rehabilitation including physiotherapy improved postoperative recovery. There are currently two registered trials investigating the use of postoperative physiotherapy for DCM. CONCLUSIONS: The literature provides insufficient evidence to make any evidence-based recommendations regarding postoperative physiotherapy use in DCM.Item Open Access Accepted version Peer-reviewed Quantification of human cardiac inorganic phosphate content in vivo by 31P-MRSI at 7T(The International Society for Magnetic Resonance in Medicine, 2018-06-19) Valkovic, Ladislav; Schmid, Albrecht Ingo; Purvis, Lucian AB; Ellis, Jane; Neubauer, Stefan; Rodgers, CT; Rodgers, Christopher [0000-0003-1275-1197]Synopsis: Determination of human cardiac Pi using 31P-MRS is challenging as the resonance frequency of Pi is concealed by a close resonating 2,3-DPG signal originating from blood. Long TR acquisition using adiabatic excitation at 7T can compensate for the rapid blood signal replacement in partially-saturated short TR scans. In order to quantify Pi concentration in vivo, knowledge about longitudinal relaxation of Pi is still required. We have measured the T1 of Pi in 4 healthy volunteers at 7T using dual-TR method and used this value to quantify cardiac Pi concentration in 8 healthy volunteers.Item Open Access Accepted version Peer-reviewed The effects of iodinated CT contrast agent on phosphorus MRSValkovic, Ladislav; Lau, Justin YC; Abdessalam, Ines; Rider, Oliver; Tyler, Damian J; Rodgers, CT; Miller, Jack JJJ; Rodgers, Christopher [0000-0003-1275-1197]Synopsis Contrast-enhanced CT examination can influence H-MRI measurements performed within 24h after the CT scan, due to a reduction in water T and T caused by the iodinated contrast agents used in CT. We have investigated whether contrast from a previous CT examination would also influence metabolic measurements made using P-MRS, by measuring the T of H and P signals in human blood. We find that iodinated CT contrast agent has no effect on phosphorus T s. Therefore, P-MRS examinations will not be influenced by prior CT (unlike H-MRI scans).Item Open Access Published version Peer-reviewed Texture Analysis of T1 weighted and fluid attenuated inversion recovery images detects abnormalities which correlate with disease progression in small vessel disease(Wolters Kluwer Health, 2018-07) Tozer, DJ; Zeestraten, E; Lawrence, AJ; Barrick, T; Markus, HS; Tozer, Daniel [0000-0002-0404-3214]; Markus, Hugh [0000-0002-9794-5996]Background and Purpose MRI techniques may be useful to assess disease severity in cerebral small vessel disease (SVD), identify those individuals who are most likely to progress to dementia, monitor disease progression and act as surrogate markers to test new therapies. Texture analysis extracts information on the relationship between signal intensities of neighbouring voxels. A potential advantage over some techniques used to characterise SVD, such as diffusion tensor imaging, is that it can be used on routine clinically obtained MR sequences. We determined whether texture parameters (TP) were abnormal in SVD, correlated with cognitive impairment, or predict cognitive decline. Methods In the prospective SCANS study we assessed TP in 121 individuals with symptomatic SVD at baseline, 99 of whom attended for repeat MRI and cognitive testing performed yearly for 3 years after which cognitive testing alone was performed for a further 2 years. Conversion to dementia was recorded for all subjects over the 5 years period. Texture analysis was performed on FLAIR and T1-weighted images. The SVD cohort was compared with 54 age matched controls scanned on the same system. Results There were highly significant differences in a number of TP between SVD cases and controls. Within the SVD population TP were highly correlated to other MRI parameters (brain volume, white matter lesion volume, lacune count). TP predicted executive function and global function at baseline and predicted conversion to dementia, after controlling for age, gender, pre-morbid IQ and other MR parameters. Conclusions TP, which can be obtained from sequences used in routine clinical imaging, are abnormal in SVD and the degree of abnormality correlates with executive dysfunction and global cognition at baseline and decline over five years. TP may be useful to assess disease severity in clinically collected data. This needs testing in data clinically acquired across multiple sites.Item Open Access Published version Peer-reviewed Using a whole-body 31P birdcage transmit coil and 16-element receive array for human cardiac metabolic imaging at 7T.(Public Library of Science (PLoS), 2017) Valkovič, Ladislav; Dragonu, Iulius; Almujayyaz, Salam; Batzakis, Alex; Young, Liam AJ; Purvis, Lucian AB; Clarke, William T; Wichmann, Tobias; Lanz, Titus; Neubauer, Stefan; Robson, Matthew D; Klomp, Dennis WJ; Rodgers, Christopher T; Valkovič, Ladislav [0000-0003-2567-3642]PURPOSE: Cardiac phosphorus magnetic resonance spectroscopy (31P-MRS) provides unique insight into the mechanisms of heart failure. Yet, clinical applications have been hindered by the restricted sensitivity of the surface radiofrequency-coils normally used. These permit the analysis of spectra only from the interventricular septum, or large volumes of myocardium, which may not be meaningful in focal disease. Löring et al. recently presented a prototype whole-body (52 cm diameter) transmit/receive birdcage coil for 31P at 7T. We now present a new, easily-removable, whole-body 31P transmit radiofrequency-coil built into a patient-bed extension combined with a 16-element receive array for cardiac 31P-MRS. MATERIALS AND METHODS: A fully-removable (55 cm diameter) birdcage transmit coil was combined with a 16-element receive array on a Magnetom 7T scanner (Siemens, Germany). Electro-magnetic field simulations and phantom tests of the setup were performed. In vivo maps of B1+, metabolite signals, and saturation-band efficiency were acquired across the torsos of eight volunteers. RESULTS: The combined (volume-transmit, local receive array) setup increased signal-to-noise ratio 2.6-fold 10 cm below the array (depth of the interventricular septum) compared to using the birdcage coil in transceiver mode. The simulated coefficient of variation for B1+ of the whole-body coil across the heart was 46.7% (surface coil 129.0%); and the in vivo measured value was 38.4%. Metabolite images of 2,3-diphosphoglycerate clearly resolved the ventricular blood pools, and muscle tissue was visible in phosphocreatine (PCr) maps. Amplitude-modulated saturation bands achieved 71±4% suppression of phosphocreatine PCr in chest-wall muscles. Subjects reported they were comfortable. CONCLUSION: This easy-to-assemble, volume-transmit, local receive array coil combination significantly improves the homogeneity and field-of-view for metabolic imaging of the human heart at 7T.Item Open Access Published version Peer-reviewed The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway.(Wiley, 2019-01) Hughes, Daniel; Mallucci, Giovanna R; Hughes, Daniel [0000-0002-9706-5163]The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signalling is mediated through three branches, PERK, IRE1, and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, while the IRE1 and ATF6 branch signalling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery. Protein misfolding neurodegenerative diseases show disruption of proteostasis as a biochemical feature. In the brains of animal models of disease and in human post mortem tissue from many of these disorders, markers of UPR induction, particularly, the PERK pathway can be observed in close association with disease progression. Recent research has revealed dysregulated UPR signalling to be a major pathogenic mechanism in neurodegeneration, and that genetic and pharmacological modulation of the PERK pathway results in potent neuroprotection. Targeting aberrant UPR signalling is the focus of new therapeutic strategies, which importantly could be beneficial across the broad spectrum of neurodegenerative diseases.Item Open Access Published version Peer-reviewed Prehospital Intubation and Outcome in Traumatic Brain Injury-Assessing Intervention Efficacy in a Modern Trauma Cohort.(Frontiers Media SA, 2018) Rubenson Wahlin, Rebecka; Nelson, David W; Bellander, Bo-Michael; Svensson, Mikael; Helmy, Adel; Thelin, Eric Peter; Helmy, Adel [0000-0002-0531-0556]; Thelin, Eric [0000-0002-2338-4364]BACKGROUND: Prehospital intubation in traumatic brain injury (TBI) focuses on limiting the effects of secondary insults such as hypoxia, but no indisputable evidence has been presented that it is beneficial for outcome. The aim of this study was to explore the characteristics of patients who undergo prehospital intubation and, in turn, if these parameters affect outcome. MATERIAL AND METHODS: Patients ≥15 years admitted to the Department of Neurosurgery, Stockholm, Sweden with TBI from 2008 through 2014 were included. Data were extracted from prehospital and hospital charts, including prospectively collected Glasgow Outcome Score (GOS) after 12 months. Univariate and multivariable logistic regression models were employed to examine parameters independently correlated to prehospital intubation and outcome. RESULTS: A total of 458 patients were included (n = 178 unconscious, among them, n = 61 intubated). Multivariable analyses indicated that high energy trauma, prehospital hypotension, pupil unresponsiveness, mode of transportation, and distance to the hospital were independently correlated with intubation, and among them, only pupil responsiveness was independently associated with outcome. Prehospital intubation did not add independent information in a step-up model versus GOS (p = 0.154). Prehospital reports revealed that hypoxia was not the primary cause of prehospital intubation, and that the procedure did not improve oxygen saturation during transport, while an increasing distance from the hospital increased the intubation frequency. CONCLUSION: In this modern trauma cohort, prehospital intubation was not independently associated with outcome; however, hypoxia was not a common reason for prehospital intubation. Prospective trials to assess efficacy of prehospital airway intubation will be difficult due to logistical and ethical considerations.Item Open Access Published version Peer-reviewed In and around the optic chiasm: a pictorial review of neuroimaging(American Society of Neuroradiology, 2019-02-01) Zaccagna, F; Pizzuti, Valentina; Barone, Damiano Giuseppe; Siotto, Paolo; Saba, Luca; Raz, Eytan; Matys, Tomasz; Massoud, Tarik; Zaccagna, Fulvio [0000-0001-6838-9532]; Barone, Damiano [0000-0002-0091-385X]; Matys, Tomasz [0000-0003-2285-5715]The optic chiasm is a key anatomical structure along the visual pathway, situated at the crossroads between optic nerves and tracts. A wide range of diseases can affect the optic chiasm and its surrounding strategic region at the base of the brain. Management strategies for optic chiasm abnormalities vary substantially, depending on the abnormalities revealed on neuroimaging. Scant attention has been paid to date to comprehensive classification of neuroimaging manifestations of optic chiasm abnormalities. We comprehensively review and present the imaging findings in a wide spectrum of pathologies originating from or involving the optic chiasm. This review will aid in differentiating the many neuroimaging appearances of lesions in this region.Item Open Access Accepted version Peer-reviewed Six-month Longitudinal Comparison of a Portable Tablet Perimeter With the Humphrey Field Analyzer.(Elsevier, 2018-06) Prea, Selwyn Marc; Kong, Yu Xiang George; Mehta, Aditi; He, Mingguang; Crowston, Jonathan G; Gupta, Vinay; Martin, Keith R; Vingrys, Algis J; Martin, Keith [0000-0002-9347-3661]PURPOSE: To establish the medium-term repeatability of the iPad perimetry app Melbourne Rapid Fields (MRF) compared to Humphrey Field Analyzer (HFA) 24-2 SITA-standard and SITA-fast programs. DESIGN: Multicenter longitudinal observational clinical study. METHODS: Sixty patients (stable glaucoma/ocular hypertension/glaucoma suspects) were recruited into a 6-month longitudinal clinical study with visits planned at baseline and at 2, 4, and 6 months. At each visit patients undertook visual field assessment using the MRF perimetry application and either HFA SITA-fast (n = 21) or SITA-standard (n = 39). The primary outcome measure was the association and repeatability of mean deviation (MD) for the MRF and HFA tests. Secondary measures were the point-wise threshold and repeatability for each test, as well as test time. RESULTS: MRF was similar to SITA-fast in speed and significantly faster than SITA-standard (MRF 4.6 ± 0.1 minutes vs SITA-fast 4.3 ± 0.2 minutes vs SITA-standard 6.2 ± 0.1 minutes, P < .001). Intraclass correlation coefficients (ICC) between MRF and SITA-fast for MD at the 4 visits ranged from 0.71 to 0.88. ICC values between MRF and SITA-standard for MD ranged from 0.81 to 0.90. Repeatability of MRF MD outcomes was excellent, with ICC for baseline and the 6-month visit being 0.98 (95% confidence interval: 0.96-0.99). In comparison, ICC at 6-month retest for SITA-fast was 0.95 and SITA-standard 0.93. Fewer points changed with the MRF, although for those that did, the MRF gave greater point-wise variability than did the SITA tests. CONCLUSIONS: MRF correlated strongly with HFA across 4 visits over a 6-month period, and has good test-retest reliability. MRF is suitable for monitoring visual fields in settings where conventional perimetry is not readily accessible.Item Open Access Accepted version Peer-reviewed Whole-body 7T 31P birdcage transmit coil driven by a 35kW RF amplifier with an integrated 30-element 31P receive array and an 8-element 1H transmit/receive array(International Society for Magnetic Resonance in Medicine) Valkovic, Ladislav; Batzakis, Alex; Ellis, Jane; Purvis, Lucian AB; Schmid, Albrecht Ingo; Robson, Matthew D; Klomp, Dennis; Rodgers, CT; Rodgers, Christopher [0000-0003-1275-1197]Synopsis: We describe our experiences implementing a whole-body transmit coil driven by a 35kW RF power amplifier, with a 30-element 31P receive array, and an 8-element 1H transmit/receive array, optimised for cardiac 31P-MRS at 7T. We describe an adaptation to the vendor’s standard SAR monitoring to monitor RF power levels up to the full 35kW output of the RFPA. This new hardware was found to achieve better 31P B1+ and SNR at the depth of the heart than other coils available in our institution. This setup promises to allow the first regionally-resolved, whole-heart 31P-MRSI studies at 7T in the near future.Item Open Access Published version Peer-reviewed Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations(F1000 Research Ltd, 2017) Barker, RA; Collins, L; Drouin-Ouellet, J; Kuan, WL; Cox, T; Barker, Roger [0000-0001-8843-7730]; Kuan, William [0000-0002-0273-1320]; Cox, Timothy [0000-0002-4951-9941]Background: Recently, the development of Parkinson’s disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.Item Open Access Accepted version Peer-reviewed Imaging the healthy human brain with hyperpolarized 13C MRI(Wiley, 2018-06-18) Grist, JT; McLean, MA; Riemer, F; Zaccagna, F; Hilborne, SF; Mason, JP; Matys, T; Graves, M; Jones, jo; Coles, AJ; Brindle, KM; Gallagher, FA; Grist, James [0000-0001-7223-4031]; McLean, Mary [0000-0002-3752-0179]; Riemer, Frank [0000-0002-3805-5221]; Zaccagna, Fulvio [0000-0001-6838-9532]; Matys, Tomasz [0000-0003-2285-5715]; Graves, Martin [0000-0003-4327-3052]; Jones, Joanna [0000-0003-4974-1371]; Brindle, Kevin [0000-0003-3883-6287]; Gallagher, Ferdia [0000-0003-4784-5230]Hyperpolarized 13C MR Spectroscopic Imaging (MRSI) can be used to probe human metabolism in vivo in real time. To date, this has been applied to studies of [1-13C] pyruvate metabolism in oncology and in the healthy human heart (1-3). Here we describe initial results from the first study to image [1-13C] pyruvate metabolism in the healthy human brain. The results show the feasibility of imaging the exchange of hyperpolarized 13C label between pyruvate and the endogenous lactate pool in the healthy brain as well as spectroscopic measurements of 13C-bicarbonate production.Item Open Access Accepted version Peer-reviewed Unambiguous detection of cardiac Pi using long TM 31P STEAM(International Society for Magnetic Resonance in Medicine, 2018-06-19) Schmid, Albrecht Ingo; Valkovic, Ladislav; Tunnicliffe, Elizabeth M; Rodgers, CT; Rodgers, Christopher [0000-0003-1275-1197]Synopsis Inorganic Phosphate is a resonance that holds important information on the metabolic state of tissues. From its resonance frequency, intracellular pH can be derived. The ratio of P to PCr or ATP are also important markers. Unlike in other tissues, myocardial P is frequently hidden underneath blood DPG signals. Using STEAM's T delay to be one cardiac cycle, blood-pool originating signals are gone and the Pi resonance is clearly visible. In 3 subjects, P signal was detected and quantified. The signal was around 4.89±0.02ppm, corresponding to a pH of 7.08±0.02. This is a breakthrough for the investigation of cardiac metabolism.Item Open Access Accepted version Peer-reviewed Reproducibility of cardiac 31P MRS at 7 T(International Society for Magnetic Resonance in Medicine, 2018-06) Ellis, Jane; Valkovic, Ladislav; Purvis, Lucian AB; Clarke, William T; Rodgers, CT; Rodgers, Christopher [0000-0003-1275-1197]Synopsis Cardiac PCr/ATP ratios measured by P MRS change in cardiovascular disease giving them value as a biomarker. We scanned 13 healthy volunteers at 7T, assessing their PCr/ATP with 6 ½ min P CSI scans. These data have better reproducibility than a 30min 3T protocol previously published by our centre. Repeated PCr/ATP measurements from subjects in this study were not significantly (P=0.83) different. Measurements were significantly different (P<0.001) from DCM patient data acquired in a previous 7T study using the same coil and pulse sequence. This data will allow us to plan future 7T P-MRS clinical studies.Item Open Access Published version Peer-reviewed Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability.(Public Library of Science (PLoS), 2018-04) Robinson, Susan W; Bourgognon, Julie-Myrtille; Spiers, Jereme G; Breda, Carlo; Campesan, Susanna; Butcher, Adrian; Mallucci, Giovanna R; Dinsdale, David; Morone, Nobuhiro; Mistry, Raj; Smith, Tim M; Guerra-Martin, Maria; Challiss, RA John; Giorgini, Flaviano; Steinert, Joern R; Steinert, Joern R [0000-0003-1640-0845]Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S-nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release.Item Open Access Published version Peer-reviewed Linking axon transport to regeneration using in vitro laser axotomy.(Medknow, 2018-03) Nieuwenhuis, Bart; Eva, Richard; Nieuwenhuis, Bart [0000-0002-2065-2271]; Eva, Richard [0000-0003-0305-0452]Spinal cord injury has devastating consequences because adult central nervous system (CNS) neurons do not regenerate their axons after injury. Two key reasons for axon regeneration failure are extrinsic inhibitory factors and a low intrinsic capacity for axon regrowth. Research has therefore focused on overcoming extrinsic growth inhibition, and enhancing intrinsic regeneration capacity. Both of these issues will need to be addressed to enable optimal repair of the injured spinal cord.Item Open Access Published version Peer-reviewed Editorial: Monitoring Pathophysiology in the Injured Brain.(Frontiers Media SA, 2018) Thelin, Eric Peter; Helmy, Adel; Nelson, David W; Marklund, Niklas; Thelin, Eric [0000-0002-2338-4364]; Helmy, Adel [0000-0002-0531-0556]Item Open Access Published version Peer-reviewed Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.(American Chemical Society (ACS), 2018-06-20) Kundel, Franziska; Hong, Liu; Falcon, Benjamin; McEwan, William A; Michaels, Thomas CT; Meisl, Georg; Esteras, Noemi; Abramov, Andrey Y; Knowles, Tuomas JP; Goedert, Michel; Klenerman, David; Kundel, Franziska [0000-0001-5013-0004]; Meisl, Georg [0000-0002-6562-7715]; Knowles, Tuomas JP [0000-0002-7879-0140]The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level. We found that tau aggregates have an intrinsic ability to amplify by filament fragmentation, and determined the doubling times for this replication process by kinetic modeling. We then simulated the spreading time for aggregates through the brain and found this to be in good agreement with both the observed time frame for spreading of pathological tau deposits in Alzheimer's disease and in experimental models of tauopathies. With this work we begin to understand the physical parameters that govern the spreading rates of tau and other amyloids through the human brain.Item Open Access Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia.(Springer Nature, 2018-04-09) Vijayakrishnan, Jayaram; Studd, James; Broderick, Peter; Kinnersley, Ben; Holroyd, Amy; Law, Philip J; Kumar, Rajiv; Allan, James M; Harrison, Christine J; Moorman, Anthony V; Vora, Ajay; Roman, Eve; Rachakonda, Sivaramakrishna; Kinsey, Sally E; Sheridan, Eamonn; Thompson, Pamela D; Irving, Julie A; Koehler, Rolf; Hoffmann, Per; Nöthen, Markus M; Heilmann-Heimbach, Stefanie; Jöckel, Karl-Heinz; Easton, Douglas F; Pharaoh, Paul DP; Dunning, Alison M; Peto, Julian; Canzian, Frederico; Swerdlow, Anthony; Eeles, Rosalind A; Kote-Jarai, ZSofia; Muir, Kenneth; Pashayan, Nora; Greaves, Mel; Zimmerman, Martin; Bartram, Claus R; Schrappe, Martin; Stanulla, Martin; Hemminki, Kari; Houlston, Richard S; PRACTICAL Consortium; Easton, Douglas [0000-0003-2444-3247]; Pharoah, Paul [0000-0001-8494-732X]; Dunning, Alison [0000-0001-6651-7166]Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 × 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 × 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology.Item Open Access Published version Peer-reviewed Psychopathic traits influence amygdala-anterior cingulate cortex connectivity during facial emotion processing(OUP, 2018-05-01) Ewbank, M; Passamonti, L; Hagan, C; Goodyer, I; Calder, A; Fairchild, G; Passamonti, Luca [0000-0002-7937-0615]; Goodyer, Ian [0000-0001-9183-0373]There is accumulating evidence that youths with antisocial behavior or psychopathic traits show deficits in facial emotion recognition, but little is known about the neural mechanisms underlying these impairments. A number of neuroimaging studies have investigated brain activity during facial emotion processing in youths with Conduct Disorder (CD) and adults with psychopathy, but few of these studies tested for group differences in effective connectivity – i.e., changes in connectivity during emotion processing. Using functional magnetic resonance imaging and psycho-physiological interaction methods, we investigated the impact of CD and psychopathic traits on amygdala activity and effective connectivity in 46 male youths with CD and 25 typically-developing controls when processing emotional faces. All participants were aged 16-21 years. Relative to controls, youths with CD showed reduced amygdala activity when processing angry or sad faces relative to neutral faces, but the groups did not significantly differ in amygdala-related effective connectivity. In contrast, psychopathic traits were negatively correlated with amygdala-ventral anterior cingulate cortex connectivity for angry versus neutral faces, but were unrelated to amygdala responses to angry or sad faces. These findings suggest that CD and psychopathic traits have differential effects on amygdala activation and functional interactions between limbic regions during facial emotion processing.