David H Miller

UCL Eastman Dental Institute, Londinium, England, United Kingdom

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Publications (193)1668.36 Total impact

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    ABSTRACT: Objective: To develop a composite MRI-based measure of motor network integrity, and determine if it explains disability better than conventional MRI measures in patients with multiple sclerosis (MS). Methods: Tract density imaging and constrained spherical deconvolution tractography were used to identify motor network connections in 22 controls. Fractional anisotropy (FA), magnetization transfer ratio (MTR), and normalized volume were computed in each tract in 71 people with relapse onset MS. Principal component analysis was used to distill the FA, MTR, and tract volume data into a single metric for each tract, which in turn was used to compute a composite measure of motor network efficiency (composite NE) using graph theory. Associations were investigated between the Expanded Disability Status Scale (EDSS) and the following MRI measures: composite motor NE, NE calculated using FA alone, FA averaged in the combined motor network tracts, brain T2 lesion volume, brain parenchymal fraction, normal-appearing white matter MTR, and cervical cord cross-sectional area. Results: In univariable analysis, composite motor NE explained 58% of the variation in EDSS in the whole MS group, more than twice that of the other MRI measures investigated. In a multivariable regression model, only composite NE and disease duration were independently associated with EDSS. Conclusions: A composite MRI measure of motor NE was able to predict disability substantially better than conventional non-network-based MRI measures.
    Neurology 08/2015; DOI:10.1212/WNL.0000000000001970 · 8.30 Impact Factor
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    ABSTRACT: Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 08/2015; 138(9):2584-95. DOI:10.1093/brain/awv209 · 10.23 Impact Factor
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    ABSTRACT: Cortical grey matter (GM) lesions are common in multiple sclerosis (MS), but little is known about their temporal evolution. We investigated this in people with relapsing-remitting (RR) and secondary progressive (SP) MS. 27 people with RRMS, and 22 with SPMS were included in this study. Phase-sensitive inversion recovery scans were acquired on 2 occasions. Cortical GM lesions were classified as intracortical (IC, only involving GM) and leucocortical (LC, mixed GM-white matter (WM)); WM lesions touching the cortex as juxtacortical (JC). On follow-up scans, new IC, LC and JC lesions were identified, and any change in classification of lesions previously observed was noted. WM lesion counts in the whole brain were assessed on PD/T2-weighted scans. Over a mean (SD) of 21.0 (5.8) months, the number of new IC lesions per person per year was greater in SPMS (1.6 (1.9)) than RRMS (0.8 (1.9)) (Mann-Whitney p=0.039). All new LC lesions arose from previously seen IC lesions (SPMS 1.4 (1.8) per person per year, and RRMS 1.1 (1.0)), and none arose de novo, or from previously seen JC lesions. Changes in cortical GM (either new IC or IC converting to LC) lesion counts did not correlate with the changes in WM lesion counts. New cortical GM lesions rarely arise from the WM and the rate of new IC lesion formation is not closely linked with WM lesion accrual. IC lesion formation appears to be more common in SPMS than RRMS. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of neurology, neurosurgery, and psychiatry 08/2015; DOI:10.1136/jnnp-2015-311102 · 5.58 Impact Factor
  • ISMRM 2015, Toronto; 06/2015
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    ABSTRACT: In this study we look at the relationship between total sodium concentration (TSC) and T2 in multiple sclerosis, both of which are sensitive to demyelination. 1H T2 increases are seen as the myelin water fraction reduces due to demyelination. A TSC increase is also expected as a result of demyelination, which causes an over-expression of sodium channels along the axon. However, increased TSC also occurs if extracellular space increases due to cell swelling or degradation. Here we look at the interaction between TSC and T2 in NAWM, NAGM, CSF, T1 and T2 lesions, in relapsing remitting and secondary progressive MS.
    ISMRM 2015, Toronto; 06/2015
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    ABSTRACT: Brain atrophy is a well established pathologically feature of multiple sclerosis (MS). Here we compare GIF, a novel segmentation technique which has not been previously applied in people with MS, to SPM12 results. Acknowledging the small number of subjects, statistical measures and qualitative assessment showed that GIF provides a relatively significant improvement in segmentation accuracy when compared to SPM12, with an improved agreement between observers (r=0.740 VS r=0.203). GIF was also found to be more robust (i.e. lower standard deviations) at estimating brain atrophy (i.e. volume fractions) on both HC and MS subjects.
    ISMRM 2015, Toronto; 06/2015
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    Hugh Kearney · David H Miller · Olga Ciccarelli
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    ABSTRACT: Multiple sclerosis (MS) is an inflammatory disorder of the CNS that affects both the brain and the spinal cord. MRI studies in MS focus more often on the brain than on the spinal cord, owing to the technical challenges in imaging this smaller, mobile structure. However, spinal cord abnormalities at disease onset have important implications for diagnosis and prognosis. Furthermore, later in the disease course, in progressive MS, myelopathy becomes the primary characteristic of the clinical presentation, and extensive spinal cord pathology-including atrophy, diffuse abnormalities and numerous focal lesions-is common. Recent spinal cord imaging studies have employed increasingly sophisticated techniques to improve detection and quantification of spinal cord lesions, and to elucidate their relationship with physical disability. Quantitative MRI measures of cord size and tissue integrity could be more sensitive to the axonal loss and other pathological processes in the spinal cord than is conventional MRI, putting quantitative MRI in a key role to elucidate the association between disability and spinal cord abnormalities seen in people with MS. In this Review, we summarize the most recent MS spinal cord imaging studies and discuss the new insights they have provided into the mechanisms of neurological impairment. Finally, we suggest directions for further and future research.
    Nature Reviews Neurology 05/2015; 11(6). DOI:10.1038/nrneurol.2015.80 · 14.10 Impact Factor
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    ABSTRACT: Background: In multiple sclerosis (MS), diffusion tensor and magnetisation transfer imaging are both abnormal in lesional and extra-lesional cortical grey matter, but differences between clinical subtypes and associations with clinical outcomes have only been partly assessed. Objective: To compare mean diffusivity, fractional anisotropy and magnetisation transfer ratio (MTR) in cortical grey matter lesions (detected using phase-sensitive inversion recovery (PSIR) imaging) and extra-lesional cortical grey matter, and assess associations with disability in relapse-onset MS. Methods: Seventy-two people with MS (46 relapsing–remitting (RR), 26 secondary progressive (SP)) and 36 healthy controls were included in this study. MTR, mean diffusivity and fractional anisotropy were measured in lesional and extra-lesional cortical grey matter. Results: Mean fractional anisotropy was higher and MTR lower in lesional compared with extra-lesional cortical grey matter. In extra-lesional cortical grey matter mean fractional anisotropy and MTR were lower, and mean diffusivity was higher in the MS group compared with controls. Mean MTR was lower and mean diffusivity was higher in lesional and extra-lesional cortical grey matter in SPMS when compared with RRMS. These differences were independent of disease duration. In multivariate analyses, MTR in extra-lesional more so than lesional cortical grey matter was associated with disability. Conclusion: Magnetic resonance abnormalities in lesional and extra-lesional cortical grey matter are greater in SPMS than RRMS. Changes in extra-lesional compared with lesional cortical grey matter are more consistently associated with disability.
    Multiple Sclerosis 05/2015; DOI:10.1177/1352458515586085 · 4.86 Impact Factor
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    ABSTRACT: Background: The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double inversion recovery (DIR) MRI, or as diffuse pathology, which can manifest as atrophy. It is, however, unclear whether the diffuse atrophy centres on focal lesions. This study aimed to determine if GM lesions and GM atrophy colocalise, and to assess their independent relationship with motor and cognitive deficits in MS. Methods: Eighty people with MS and 30 healthy controls underwent brain volumetric T1-weighted and DIR MRI at 3 T, and had a comprehensive neurological and cognitive assessment. Probability mapping of GM lesions marked on the DIR scans and voxel- based morphometry (assessing GM atrophy) were carried out. The associations of GM lesion load and GM volume with clinical scores were tested. Results: DIR-visible GM lesions were most commonly found in the right cerebellum and most apparent in patients with primary progressive MS. Deep GM structures appeared largely free from lesions, but showed considerable atrophy, particularly in the thalamus, caudate, pallidum and putamen, and this was most apparent in secondary progressive patients with MS. Very little co-localisation of GM atrophy and lesions was seen, and this was generally confined to the cerebellum and postcentral gyrus. In both regions, GM lesions and volume independently correlated with physical disability and cognitive performance. Conclusions: DIR-detectable GM lesions and GM atrophy do not significantly overlap in the brain but, when they do, they independently contribute to clinical disability.
    Journal of neurology, neurosurgery, and psychiatry 04/2015; DOI:10.1136/jnnp-2014-310142 · 5.58 Impact Factor
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    ABSTRACT: Lesions in the corpus callosum (CC) are important radiological clues to the diagnosis of multiple sclerosis (MS), but may also occur in other neuroinflammatory and non-neuroinflammatory conditions. In this article, we discuss the radiological features of lesions within the CC in MS and other central nervous system inflammatory and acquired demyelinating diseases. An understanding of the appearance and location of lesions in the CC is important not only for accurate diagnosis and treatment of these various conditions, but as it also provides insights into pathogenesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of neurology, neurosurgery, and psychiatry 04/2015; DOI:10.1136/jnnp-2014-309649 · 5.58 Impact Factor
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    ABSTRACT: In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ∼1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 03/2015; 138(5). DOI:10.1093/brain/awv065 · 10.23 Impact Factor
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    ABSTRACT: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment. © 2015 American Academy of Neurology.
    Neurology 02/2015; 84(11). DOI:10.1212/WNL.0000000000001360 · 8.30 Impact Factor
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    ABSTRACT: Background: In multiple sclerosis (MS), recent work suggests that cervical cord atrophy is more consistently correlated with physical disability than brain white matter lesion load and atrophy. Although spinal cord imaging has not been routinely obtained in many clinical trial and research studies, brain volumetric imaging usually has and includes the upper cervical cord. Objectives: Using volumetric T1-weighted brain images, we investigated cross-sectional area measures in the uppermost cervical cord and compared them with areas at the standard C2/3 level. Methods: Using T1-weighted brain scans from 13 controls and 37 people with MS, and an active surface technique, cross-sectional area was measured over 5 mm and 1 mm cord segments at C2/3, below the level of odontoid peg, and 2 cm and 2.5 cm below the pons. Brain volume was also measured. Results: Cord area measurements were most reliable in a 5 mm segment 2.5 cm below the pons (inter-rater coefficient of variation 1.5%, intraclass correlation coefficient 0.99). Cord area at this level correlated more with that at C2/3 area than with brain volume (r=0.811 with C2/3, r=0.502 with brain volume). Conclusion: Whereas the standard C2/3 level is often not within the field of view on brain images, the level 2.5 cm below the pons usually is, and measurement at this level may be a good way to investigate upper cervical cord atrophy when only brain images are available.
    Multiple Sclerosis and Related Disorders 01/2015; 4(1-1):52-57. DOI:10.1016/j.msard.2014.11.004
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    ABSTRACT: To investigate whether spinal cord (SC) lesion load, when quantified on axial images with high in-plane resolution, is associated with disability in multiple sclerosis (MS). Twenty-eight healthy controls and 92 people with MS had cervical SC 3T MRI with axial phase sensitive inversion recovery, T2, and magnetization transfer (MT) sequences. We outlined all visible focal lesions from C2 to C4 to obtain lesion load and also measured upper cervical cord area. We measured MT ratio in normal-appearing cord tissue and in lesions. Disability was recorded using the Expanded Disability Status Scale (EDSS) and MS Functional Composite. We used linear regression models to determine associations with disability. SC lesion load was significantly higher in both secondary progressive MS (SPMS) (p = 0.008) and primary progressive MS (PPMS) (p = 0.02) compared to relapsing-remitting MS (RRMS); in each comparison, adjustment was made for age, sex, and brain volume. These differences were not evident when EDSS was added as a covariate. SC area was significantly lower in both SPMS (p < 0.001) and PPMS (p = 0.009) compared to RRMS. In a multiple regression model, cord lesion load (p < 0.001), cord area (p = 0.003), age (p < 0.001), and sex (p = 0.001) were independently associated with EDSS (R(2) = 0.58). Cord lesion load (p = 0.003), cord area (p = 0.034), and brain parenchymal fraction (p = 0.007) were independently associated with the 9-hole peg test (R(2) = 0.42). When quantified on axial MRI with high in-plane resolution, upper cervical cord lesion load is significantly and independently correlated with physical disability and is higher in progressive forms of MS than RRMS. © 2014 American Academy of Neurology.
    Neurology 12/2014; 84(4). DOI:10.1212/WNL.0000000000001186 · 8.30 Impact Factor
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    Wallace J. Brownlee · David H. Miller
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    ABSTRACT: The most common presentation of multiple sclerosis (MS) is with a clinically isolated syndrome (CIS) affecting the optic nerves, brainstem or spinal cord. Two thirds of patients with CIS will have further episodes of neurological dysfunction and convert to relapsing-remitting MS, while the remaining patients have a monophasic illness, at least clinically. Abnormalities on a baseline MRI scan predict the subsequent development of MS in patients with CIS. In the long term, about 80% of patients with an abnormal MRI convert to MS compared with 20% with a normal MRI. For patients who develop MS the long term prognosis is varied. After 20 years, almost half will have developed secondary progressive MS, while around one third have a benign disease course with little physical disability. Disease-modifying treatments delay conversion to MS in selected CIS patients with abnormal MRI but an effect on long term disability has not been demonstrated. In this review we discuss recent advances in the diagnosis, management and prognostication of patients with CIS.
    Journal of Clinical Neuroscience 12/2014; 21(12). DOI:10.1016/j.jocn.2014.02.026 · 1.32 Impact Factor
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    ABSTRACT: Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation, but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis. Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests, structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that give clinical meaning to the structure-function correlations that are unique to the afferent visual pathway. Abnormal eye movements also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals, to review the state of the field and identify areas for future research. We review data and principles to help us understand the importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.
    Brain 11/2014; 138(1). DOI:10.1093/brain/awu335 · 10.23 Impact Factor
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    ABSTRACT: The McDonald criteria allow multiple sclerosis (MS) to be diagnosed in patients with a clinically isolated syndrome (CIS) who have MRI evidence of dissemination in time and space.1-3 There have been successive versions of the criteria in 2001,1 20052 and 20103 with different requirements for dissemination in time and space. Although each version has been shown to have a high sensitivity and specificity for the development of clinically-definite MS (CDMS), few studies have investigated how much sooner4 and how more often5 MS can be diagnosed in patients with CIS using the McDonald criteria. We recruited 178 patients with CIS presenting to Moorfields Eye Hospital and the National Hospital for Neurology and Neurosurgery between 1995 and 2004. The study was approved by ethics committees at both hospitals. Patients were seen at baseline, then for follow-up after 3 months, 1 year, 3 years and 6 years. At each study visit informed consent was obtained. Patients were assessed with a detailed review of neurological symptoms and neurological examination. Relapses were recorded at study visits, but patients were also encouraged to contact the research team at the time of new neurological symptoms. MRI of the brain and whole spine was obtained at each visit on the same 1.5 T Signa scanner, as described elsewhere.6 Each scan was reviewed by a neuroradiologist blinded to the patient's clinical status. The number, location and activity (ie, gadolinium enhancement) of T2 lesions was recorded. During follow-up CDMS was defined according … [Full text of this article]
    Journal of Neurology Neurosurgery & Psychiatry 11/2014; DOI:10.1136/jnnp-2014-308675 · 5.58 Impact Factor
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    ABSTRACT: Objectives: To investigate whether (1) there were differences between HLA-DRB1∗15-positive and -negative patients at baseline, and (2) HLA-DRB1∗15-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow-up, compared with HLA-DRB1∗15-negative patients. Methods: HLA-DRB1∗15 typing was performed in 41 patients with primary progressive multiple sclerosis (PPMS) who were recruited within 5 years of symptom onset. All patients and 18 healthy controls were studied clinically and with MRI at baseline, and every 6 months for 3 years, and then at 5 years. Magnetization transfer ratio parameters and volumes for brain gray matter and normal-appearing white matter, brain T2 lesion load, and spinal cord cross-sectional area were obtained. Patient disability was assessed at each visit using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite subscores. Results: There were no significant differences between HLA-DRB1∗15-positive and -negative patients at baseline. HLA-DRB1∗15-positive patients showed a greater decline in brain magnetization transfer ratio for gray matter and normal-appearing white matter (both p 5 0.005) than HLA-DRB1∗15-negative patients over 5 years, while the same parameters did not change over time in healthy controls. HLA-DRB1∗15-positive patients also showed a trend toward a faster increase in brain T2 lesion load than HLA-DRB1∗15-negative patients (0.29 [95% confidence interval 0.20-0.38] vs 0.21 [0.13-0.30] mL/mo, p 5 0.085) and higher T2 lesion volumes at all time points (average difference [95% confidence interval]: 10.58 mL [7.09-14.07], p , 0.001) during the follow-up, after adjusting for disease duration. Conclusions: These findings suggest that HLA-DRB1∗15 influences the progression of brain pathology in PPMS.
    Neurology 10/2014; 83(19). DOI:10.1212/WNL.0000000000000959 · 8.30 Impact Factor
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    ABSTRACT: Histopathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases and recent research has suggested the use of magnetic resonance imaging (MRI) as a promising tool for in vivo assessment of the upper spinal cord. However, many neurological conditions would benefit from quantitative assessment of tissue integrity at different levels and relatively little work has been done, mainly due to technical challenges associated with imaging the lower spinal cord. In this study, the value of the lumbosacral enlargement (LSE) as an intrinsic imaging biomarker was determined by exploring the feasibility of obtaining within it reliable GM and WM cross-sectional area (CSA) measurements by means of a commercially available MRI system at 3 tesla (T). 10 healthy volunteers (mean age 27.5 years, 6 female) gave written informed consent and high resolution images of the LSE were acquired and analysed using an optimised MRI acquisition and analysis protocol. GM and WM mean CSA measurements were obtained from a 15 mm section at the level of the LSE and the reproducibility of the measurements was determined by means of scan-rescan, intra- and inter-observer assessments. Mean (±SD) LSE cross-sectional area (LSE-CSA) was 62.3 (±4.1) mm2 and mean (±SD) LSE grey matter cross-sectional area (LSE-GM-CSA) was 19.8 (±3.3) mm2. The mean scan-rescan, intra- and inter-observer % coefficient of variation (COV) for measuring the LSE-CSA were 2%, 2% and 2.5%, respectively and for measuring the LSE-GM-CSA were 7.8%, 8% and 8.6%, respectively. This study has shown that the LSE can be used reliably as an intrinsic imaging biomarker. The method presented here can be potentially extended to study the LSE in the diseased state and could provide a solid foundation for subsequent multi-parametric MRI investigations.
    PLoS ONE 08/2014; 9(8):e105544. DOI:10.1371/journal.pone.0105544 · 3.23 Impact Factor
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    ABSTRACT: Objective Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.Methods This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.
    08/2014; 1(8). DOI:10.1002/acn3.91

Publication Stats

11k Citations
1,668.36 Total Impact Points

Institutions

  • 2009–2015
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2014
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2013–2014
    • University of Otago
      • Department of Medicine (Dunedin)
      Taieri, Otago, New Zealand
  • 2007–2014
    • London School of Hygiene and Tropical Medicine
      • Department of Medical Statistics
      Londinium, England, United Kingdom
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • University of Texas Southwestern Medical Center
      • Division of Neuro-oncology
      Dallas, TX, United States
    • Università di Pisa
      Pisa, Tuscany, Italy
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
    • Protium MS
      Дэрсбёри, England, United Kingdom
  • 2000–2014
    • University College London
      • • Department of Neuroinflammation
      • • Institute of Neurology
      Londinium, England, United Kingdom
  • 2011–2013
    • University College London Hospitals NHS Foundation Trust
      • Department of Neurosurgery (National Hospital for Neurology and Neurosurgery)
      Londinium, England, United Kingdom
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2002–2012
    • London Research Institute
      Londinium, England, United Kingdom
    • Otto-von-Guericke-Universität Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 2010
    • Queen Mary, University of London
      Londinium, England, United Kingdom
  • 2003
    • University of Leicester
      Leiscester, England, United Kingdom
  • 1996
    • University of Milan
      • Department of Neurological Sciences
      Milano, Lombardy, Italy