600 results found
Zarei M, Beckmann CF, Binnewijzend MAA, et al., 2013, Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease, NEUROIMAGE, Vol: 66, Pages: 28-35, ISSN: 1053-8119
Douaud G, Menke RAL, Gass A, et al., 2013, Brain Microstructure Reveals Early Abnormalities more than Two Years prior to Clinical Progression from Mild Cognitive Impairment to Alzheimer's Disease, JOURNAL OF NEUROSCIENCE, Vol: 33, Pages: 2147-2155, ISSN: 0270-6474
Inkster B, Strijbis EMM, Vounou M, et al., 2013, Histone deacetylase gene variants predict brain volume changes in multiple sclerosis, NEUROBIOLOGY OF AGING, Vol: 34, Pages: 238-247, ISSN: 0197-4580
Matthews PM, Filippini N, Douaud G, 2013, Brain Structural and Functional Connectivity and the Progression of Neuropathology in Alzheimer's Disease, JOURNAL OF ALZHEIMERS DISEASE, Vol: 33, Pages: S163-S172, ISSN: 1387-2877
Matthews PM, 2013, Clinical imaging in drug development, Drug Discovery and Development: Technology in Transition, Pages: 259-274, ISBN: 9780702042997
Owen D, Guo Q, Colasanti A, et al., 2013, Determination of [11C]PBR28 binding potential in vivo: A first human TSPO occupancy study., Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI)
Libri V, Brown AP, Gambarota G, et al., 2012, A Pilot Randomized, Placebo Controlled, Double Blind Phase I Trial of the Novel SIRT1 Activator SRT2104 in Elderly Volunteers, PLoS ONE, Vol: 7, ISSN: 1932-6203
Background:SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD+-dependent deacetylaseinvolved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucosemetabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderlyvolunteers.Methods:Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days.Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamicendpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI)for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magneticresonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity.Results:SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally.Mean Tmax was 2–4 hours with elimination half-life of 15–20 hours. Serum cholesterol, LDL levels and triglyceridesdecreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for morerapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent withincreased mitochondrial oxidative phosphorylation.Conclusions:SRT2104 can be safely administered in elderly individuals and has biological effects in humans that areconsistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful indose selection for future clinical trials in patients.
Matthews PM, Filippini N, Douaud G, 2012, Brain structural and functional connectivity and the progression of neuropathology in Alzheimer's disease, ISBN: 9781614991533
In our contribution to this special issue focusing on advances in Alzheimer's disease (AD) research since the centennial, we will briefly review some of our own studies applying magnetic resonance imaging (MRI) measures of function and connectivity for characterization of genetic contributions to the neuropathology of AD and as candidate biomarkers. We review how functional MRI during both memory encoding and at rest is able to define APOE4 genotype-dependent physiological changes decades before potential development of AD and demonstrate changes distinct from those with healthy aging. More generally, imaging provides a powerful quantitative measure of phenotype for understanding associations arising from whole genome studies in AD. Structural connectivity measures derived from diffusion tensor MRI (DTI) methods offer additional markers of neuropathology arising from the secondary changes in axonal caliber and myelination that accompany decreased neuronal activity and neurodegeneration. We illustrate applications of DTI for more finely mapping neurodegenerative changes with AD in the thalamus in vivo and for defining neuropathological changes in the white matter itself. The latter efforts have highlighted how sensitivity to the neuropathology can be enhanced by using more specific DTI measures and interpreting them relative to knowledge of local white matter anatomy in the healthy brain. Together, our studies and related work are helping to establish the exciting potential of a new range of MRI methods as neuropathological measures and as biomarkers of disease progression. © 2013 The authors and IOS Press. All rights reserved.
Gelineau-Morel R, Tomassini V, Jenkinson M, et al., 2012, The effect of hypointense white matter lesions on automated gray matter segmentation in multiple sclerosis, HUMAN BRAIN MAPPING, Vol: 33, Pages: 2802-2814, ISSN: 1065-9471
Tomassini V, Matthews PM, Thompson AJ, et al., 2012, Neuroplasticity and functional recovery in multiple sclerosis, NATURE REVIEWS NEUROLOGY, Vol: 8, Pages: 635-646, ISSN: 1759-4758
Fleming IN, Whelan M, Baxendale R, et al., 2012, Positron emission tomography radiopharmaceutical studies in humans: a guide to regulations for academic researchers, NUCLEAR MEDICINE COMMUNICATIONS, Vol: 33, Pages: 899-906, ISSN: 0143-3636
Allen N, Sudlow C, Downey P, et al., 2012, UK Biobank: Current status and what it means for epidemiology, HEALTH POLICY AND TECHNOLOGY, Vol: 1, Pages: 123-126, ISSN: 2211-8837
Colasanti A, Guo Q, Onega M, et al., 2012, [F-18]PBR111 binding in multiple sclerosis: relationship to age and clinical variables, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S22-S22, ISSN: 0271-678X
Politis M, Giannetti P, Su P, et al., 2012, Increased PK11195 PET binding in the cortex of patients with MS correlates with disability, NEUROLOGY, Vol: 79, Pages: 523-530, ISSN: 0028-3878
Tomassini V, Johansen-Berg H, Jbabdi S, et al., 2012, Relating Brain Damage to Brain Plasticity in Patients With Multiple Sclerosis, NEUROREHABILITATION AND NEURAL REPAIR, Vol: 26, Pages: 581-593, ISSN: 1545-9683
Strijbis E, Inkster B, Vounou M, et al., 2012, Glutamate gene polymorphisms predict brain volumes in multiple sclerosis, Multiple Sclerosis Journal
Newbould RD, Miller SR, Toms LD, et al., 2012, T2* measurement of the knee articular cartilage in osteoarthritis at 3T, JOURNAL OF MAGNETIC RESONANCE IMAGING, Vol: 35, Pages: 1422-1429, ISSN: 1053-1807
De Silva A, Salem V, Matthews PM, et al., 2012, The Use of Functional MRI to Study Appetite Control in the CNS, EXPERIMENTAL DIABETES RESEARCH, Vol: 2012, ISSN: 1687-5214
Functional magnetic resonance imaging (fMRI) has provided the opportunity to safely investigate the workings of the humanbrain. This paper focuses on its use in the field of human appetitive behaviour and its impact in obesity research. In the presentabsence of any safe or effective centrally acting appetite suppressants, a better understanding of how appetite is controlled is vitalfor the development of new antiobesity pharmacotherapies. Early functional imaging techniques revealed an attenuation of brainreward area activity in response to visual food stimuli when humans are fed—in other words, the physiological state of hungersomehow increases the appeal value of food. Later studies have investigated the action of appetite modulating hormones on thefMRI signal, showing how the attenuation of brain reward region activity that follows feeding can be recreated in the fasted state bythe administration of anorectic gut hormones. Furthermore, differences in brain activity between obese and lean individuals haveprovided clues about the possible aetiology of overeating. The hypothalamus acts as a central gateway modulating homeostatic andnonhomeostatic drives to eat. As fMRI techniques constantly improve, functional data regarding the role of this small but hugelyimportant structure in appetite control is emerging.
Matthews PM, 2012, An introduction to functional magnetic resonance imaging of the brain, Functional Magnetic Resonance Imaging: An Introduction to Methods, ISBN: 9780192630711
© Oxford University Press 2001. All rights reserved. This chapter provides an overview of functional magnetic resonance imaging (fMRI) methods and applications, highlighting key concepts and strategies, and includes the full range of techniques by which physiological changes accompanying brain activity are defined. It focuses on the changes in blood oxygenation and flow that have been used for the functional magnetic resonance imaging methods. Direct imaging of the blood flow response using perfusion MRI is also discussed. The study furthermore deals with elegant methods that have been developed and allow an extension of this simple concept for one-dimensional imaging into methods for multi-slice two-dimensional or threedimensional imaging. It outlines the major issues in statistical analysis for fMRI and addresses ways in which the data can be prepared for analysis to minimize artefacts and maximize sensitivity for the detection of activation changes. Finally, the chapter discusses the various applications of fMRI in neuroscience.
Jezzard P, Matthews PM, Smith SM, 2012, Functional magnetic resonance imaging: An introduction to methods, ISBN: 9780192630711
© Oxford University Press 2001. All rights reserved. This book provides an introduction to functional magnetic resonance imaging (fMRI), the scanning technique that allows the mapping of active processes within the brain. There are six sections to the book, with chapters from an international team. Part I provides a broad overview of the field and sets the context. Part II describes the physiological and physical background to fMRI, including coverage of the hardware required and pulse-sequence selection. Practical issues involving experimental design of the paradigms, psycho-physical stimulus delivery, and subject response are covered in Part III, followed by a comprehensive treatment of data analysis in Part IV. Part V deals with practical applications of the technique in the field of neuroscience and in clinical practice. The final section describes how fMRI can be integrated with other neuro-electromagnetic functional mapping techniques.
Inkster B, Rao AW, Ridler K, et al., 2012, Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's disease, NEUROBIOLOGY OF AGING, Vol: 33, Pages: 457-465, ISSN: 0197-4580
Filippini N, Nickerson LD, Beckmann CF, et al., 2012, Age-related adaptations of brain function during a memory task are also present at rest, NEUROIMAGE, Vol: 59, Pages: 3821-3828, ISSN: 1053-8119
Gupta RK, Newbould RD, Matthews PM, 2012, Methods of measuring lung water, Journal of the Intensive Care Society, Vol: 13, Pages: 209-215, ISSN: 1751-1437
Pulmonary oedema can result from both cardiogenic and non-cardiogenic aetiologies and is a cause of considerable morbidity and mortality. Accurate methods of quantifying pulmonary oedema are needed for both clinical and research purposes. Applications could include early recognition, and thus prevention, of impending decompensation in heart failure patients, guidance of fluid management in patients with established pulmonary oedema, and as a pharmacodynamic outcome measure for early clinical trials of drugs for the treatment of pulmonary oedema. Magnetic resonance imaging, computed tomography, positron emission tomography, electrical impedance, and thermodilution methods have all been used with the aim of measuring lung water. These methods differ in their accuracy, cost, ionising radiation dose, invasiveness, portability, and ability to provide dynamic measures. To date, none have been established as a 'gold standard' clinical measurement to improve clinical outcomes or to assist drug development. This review aims to discuss each of these methods in turn, focussing on advantages, limitations, and possible future development and applications. © The Intensive Care Society 2012.
Functional magnetic resonance imaging has become a powerful tool to investigate the neuroendocrinology of appetite. In a recent study, we demonstrated that the brain activation pattern seen following the infusion of the anorectic gut hormones PYY3-36and GLP-17-36 amideto fasted individuals resembles the brain activation pattern seen in the physiological satiated state. This commentary discusses the significance of these findings and compares them with other landmark studies in the field, with specific reference to the brain areas involved in appetite regulation. We highlight the importance of this type of research in order to pave the way for the development of efficacious and safe anti-obesity therapies.
Newbould RD, Miller SR, Tielbeek JAW, et al., 2012, Reproducibility of sodium MRI measures of articular cartilage of the knee in osteoarthritis, OSTEOARTHRITIS AND CARTILAGE, Vol: 20, Pages: 29-35, ISSN: 1063-4584
Matthews PM, Rabiner EA, Passchier J, et al., 2012, Positron emission tomography molecular imaging for drug development, Br J Clin Pharmacol, Vol: 73, Pages: 175-186, ISSN: 1365-2125
Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.
Colasanti A, Searle GE, Long CJ, et al., 2012, Endogenous opioid release in the human brain reward system induced by acute amphetamine administration, Biol Psychiatry, Vol: 72, Pages: 371-377, ISSN: 1873-2402
BACKGROUND: We aimed to demonstrate a pharmacologically stimulated endogenous opioid release in the living human brain by evaluating the effects of amphetamine administration on [(11)C]carfentanil binding with positron emission tomography (PET). METHODS: Twelve healthy male volunteers underwent [(11)C]carfentanil PET before and 3 hours after a single oral dose of d-amphetamine (either a "high" dose, .5 mg/kg, or a sub-pharmacological "ultra-low" dose, 1.25 mg total dose or approximately .017 mg/kg). Reductions in [(11)C]carfentanil binding from baseline to post-amphetamine scans (DeltaBP(ND)) after the "high" and "ultra-low" amphetamine doses were assessed in 10 regions of interest. RESULTS: [(11)C]carfentanil binding was reduced after the "high" but not the "ultra-low" amphetamine dose in the frontal cortex, putamen, caudate, thalamus, anterior cingulate, and insula. CONCLUSIONS: Our findings indicate that oral amphetamine administration induces endogenous opioid release in different areas of human brain, including basal ganglia, frontal cortex areas, and thalamus. The combination of an amphetamine challenge and [(11)C]carfentanil PET is a practical and robust method to probe the opioid system in the living human brain.
Cole DM, Beckmann CF, Searle GE, et al., 2012, Orbitofrontal connectivity with resting-state networks is associated with midbrain dopamine D3 receptor availability, Cereb Cortex, Vol: 22, Pages: 2784-2793, ISSN: 1460-2199
Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed brain networks in processes relevant for these diseases. This potential conjunction between molecular and functional markers has not, however, been tested directly. Here, we used a novel combination of [(11)C]-(+)-PHNO positron emission tomography and resting-state functional magnetic resonance imaging in the same healthy individuals to investigate whether differences in midbrain D3R availability are associated with functional interactions between large-scale networks and regions involved in reward processing and cognition. High midbrain D3R availability was associated with reduced functional connectivity between orbitofrontal cortex (OFC) and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry and the "default mode" network, which showed greater connectivity with OFC in individuals with high D3R availability. These findings demonstrate that differential interactions between OFC and networks implicated in cognitive control and reward are associated with midbrain D3R availability, consistent with the hypothesis that dopamine D3R signaling is an important molecular pathway underlying goal-directed behavior.
Owen DR, Yeo AJ, Gunn RN, et al., 2012, An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28, J Cereb Blood Flow Metab, Vol: 32, Pages: 1-5, ISSN: 1559-7016
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 x 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Stagg CJ, Bachtiar V, O'Shea J, et al., 2011, Cortical activation changes underlying stimulation-induced behavioural gains in chronic stroke, BRAIN, Vol: 135, Pages: 276-284, ISSN: 0006-8950
Transcranial direct current stimulation, a form of non-invasive brain stimulation, is showing increasing promise as an adjuncttherapy in rehabilitation following stroke. However, although significant behavioural improvements have been reported inproof-of-principle studies, the underlying mechanisms are poorly understood. The rationale for transcranial direct current stimu-lation as therapy for stroke is that therapeutic stimulation paradigms increase activity in ipsilesional motor cortical areas, butthis has not previously been directly tested for conventional electrode placements. This study was performed to test directlywhether increases in ipsilesional cortical activation with transcranial direct current stimulation are associated with behaviouralimprovements in chronic stroke patients. Patients at least 6 months post-first stroke participated in a behavioural experiment(n= 13) or a functional magnetic resonance imaging experiment (n= 11), each investigating the effects of three stimulationconditions in separate sessions: anodal stimulation to the ipsilesional hemisphere; cathodal stimulation to the contralesionalhemisphere; and sham stimulation. Anodal (facilitatory) stimulation to the ipsilesional hemisphere led to significant improve-ments (5–10%) in response times with the affected hand in both experiments. This improvement was associated with anincrease in movement-related cortical activity in the stimulated primary motor cortex and functionally interconnected regions.Cathodal (inhibitory) stimulation to the contralesional hemisphere led to a functional improvement only when compared withsham stimulation. We show for the first time that the significant behavioural improvements produced by anodal stimulationto the ipsilesional hemisphere are associated with a functionally relevant increase in activity within the ipsilesional primary
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