David H Miller

WWF United Kingdom, Londinium, England, United Kingdom

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Publications (181)1549.14 Total impact

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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; 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.
    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; 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: 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.
    Neurology 10/2014; 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 · 3.53 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
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    ABSTRACT: The mechanisms underlying the pathogenesis of multiple sclerosis induce the changes that underpin relapse-associated and progressive disability. Disease mechanisms can be investigated in preclinical models and patients with multiple sclerosis by molecular and metabolic imaging techniques. Many insights have been gained from such imaging studies: persisting inflammation in the absence of a damaged blood–brain barrier, activated microglia within and beyond lesions, increased mitochondrial activity after acute lesions, raised sodium concentrations in the brain, increased glutamate in acute lesions and normal-appearing white matter, different degrees of demyelination in different patients and lesions, early neuronal damage in grey matter, and early astrocytic proliferation and activation in lesions and white matter. Clinical translation of molecular and metabolic imaging and extension of these techniques will enable the assessment of novel drugs targeted at these disease mechanisms, and have the potential to improve health outcomes through the stratification of patients for treatments.
    The Lancet Neurology 08/2014; 13(8). DOI:10.1016/S1474-4422(14)70101-2 · 21.82 Impact Factor
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    ABSTRACT: Neuropathological studies in multiple sclerosis have suggested that meningeal inflammation in the brain may be linked to disease progression. Inflammation in the spinal cord meninges has been associated with axonal loss, a pathological substrate for disability. Quantitative magnetic resonance imaging facilitates the investigation of spinal cord microstructure by approximating histopathological changes. We acquired structural and quantitative imaging of the cervical spinal cord from which we calculated magnetization transfer ratio in the outer spinal cord-an area corresponding to the expected location of the pia mater and subpial region-and in spinal cord white and grey matter. We studied 26 healthy controls, 22 people with a clinically isolated syndrome, 29 with relapsing-remitting, 28 with secondary-progressive and 28 with primary-progressive multiple sclerosis. Magnetization transfer ratio values in the outermost region of the spinal cord were higher than the white matter in controls and patients: controls (51.35 ± 1.29 versus 49.87 ± 1.45, P < 0.01), clinically isolated syndrome (50.46 ± 1.39 versus 49.13 ± 1.19, P < 0.01), relapsing-remitting (48.86 ± 2.89 versus 47.44 ± 2.70, P < 0.01), secondary-progressive (46.33 ± 2.84 versus 44.75 ± 3.10, P < 0.01) and primary-progressive multiple sclerosis (46.99 ± 3.78 versus 45.62 ± 3.40, P < 0.01). In linear regression models controlling for cord area and age, higher outer spinal cord magnetization transfer ratio values were seen in controls than all patient groups: clinically isolated syndrome (coefficient = -0.32, P = 0.03), relapsing-remitting (coefficient = -0.48, P < 0.01), secondary-progressive (coefficient = -0.51, P < 0.01) and primary-progressive multiple sclerosis (coefficient = -0.38, P < 0.01). In a regression analysis correcting for age and cord area, magnetization transfer ratio values in the outer cord were lower in relapsing-remitting multiple sclerosis compared with clinically isolated syndrome (coefficient = -0.28, P = 0.02), and both primary and secondary-progressive compared to relapsing-remitting multiple sclerosis (coefficients = -0.29 and -0.24, respectively, P = 0.02 for both). In the clinically isolated syndrome and relapsing-remitting multiple sclerosis groups, outer cord magnetization transfer ratio was decreased in the absence of significant cord atrophy. In a multivariate regression analysis an independent association was seen between outer cord magnetization transfer ratio and cord atrophy (coefficient = 0.40, P < 0.01). Our in vivo imaging observations suggest that abnormalities in a region involving the pia mater and subpial cord occur early in the course of multiple sclerosis and are more marked in those with a progressive course.
    Brain 06/2014; DOI:10.1093/brain/awu171 · 10.23 Impact Factor
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    ABSTRACT: The prevalence of MS in New Zealand in 2006 was 73.2 (age standardized per 100,000) while for those with indigenous Māori ancestry it was 3.6 times lower at 20.6. Earlier regional surveys (1968-2001) all reported much lower, or zero, prevalence for Māori than European. There was no evidence for differences in MS between those with and without Māori ancestry in either clinical features or latitude, confirming that Māori ancestry does not produce the reported increase in prevalence with latitude. It is likely that prevalence is increasing in low risk Māori; however, MS prognosis is independent of Māori ancestry.
    Multiple Sclerosis 05/2014; 20(14). DOI:10.1177/1352458514535130 · 4.86 Impact Factor
  • David H Miller
    JAMA Neurology 05/2014; 71(7). DOI:10.1001/jamaneurol.2014.896 · 7.01 Impact Factor
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    ABSTRACT: Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures.
    Journal of neurology, neurosurgery, and psychiatry 04/2014; 85(12). DOI:10.1136/jnnp-2014-307650 · 5.58 Impact Factor
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    ABSTRACT: PURPOSE: To identify an improved method for measuring spinal cord cross-sectional area (CSA) using magnetic resonance imaging (MRI) in multiple sclerosis (MS). MATERIALS AND METHODS: MRI was performed on 15 controls and 15 MS patients and repeated in nine controls and nine patients after 6 months. At this timepoint, an additional scan was acquired to evaluate scan-rescan reproducibility. Two sequences were acquired in the cervical cord: 3D phase sensitive inversion recovery (PSIR) and 3D magnetization prepared rapid acquisition T1-weighted gradient echo. CSA was outlined at C2-C3 using two methods: a semiautomated edge detection method and active surface model (ASM). We evaluated reproducibility for all combinations of sequences and analysis methods using coefficient of variation (COV) and intraclass correlation coefficient and performed sample size calculations for clinical trials to reduce longitudinal cord atrophy. RESULTS: PSIR/ASM combination provided the lowest values of COV for intrarater, interrater, scan-rescan reproducibility (0.002%, 0.03%, and 0.1% respectively). At 6-month follow-up no significant changes were seen in CSA of controls, and a trend towards significance was observed in patients. CONCLUSION: PSIR/ASM proved more reproducible than established methods of evaluating CSA in MS and also provides the lowest number of subjects per arm for 6-month and 1-year clinical trials. J. Magn. Reson. Imaging 2013. © 2013 Wiley Periodicals, Inc.
    Journal of Magnetic Resonance Imaging 03/2014; 39(3). DOI:10.1002/jmri.24194 · 2.79 Impact Factor
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    ABSTRACT: We characterized metabolic changes along the cortico-spinal tract (CST) in multiple sclerosis (MS) patients using a novel application of chemical shift imaging (CSI) and considering the spatial variation of metabolite levels. Thirteen relapsing-remitting (RR) and 13 primary-progressive (PP) MS patients and 16 controls underwent (1) H-MR CSI, which was applied to coronal-oblique scans to sample the entire CST. The concentrations of the main metabolites, i.e., N-acetyl-aspartate, myo-Inositol (Ins), choline containing compounds (Cho) and creatine and phosphocreatine (Cr), were calculated within voxels placed in regions where the CST is located, from cerebral peduncle to corona radiata. Differences in metabolite concentrations between groups and associations between metabolite concentrations and disability were investigated, allowing for the spatial variability of metabolite concentrations in the statistical model. RRMS patients showed higher CST Cho concentration than controls, and higher CST Ins concentration than PPMS, suggesting greater inflammation and glial proliferation in the RR than in the PP course. In RRMS, a significant, albeit modest, association between greater Ins concentration and greater disability suggested that gliosis may be relevant to disability. In PPMS, lower CST Cho and Cr concentrations correlated with greater disability, suggesting that in the progressive stage of the disease, inflammation declines and energy metabolism reduces. Attention to the spatial variation of metabolite concentrations made it possible to detect in patients a greater increase in Cr concentration towards the superior voxels as compared to controls and a stronger association between Cho and disability, suggesting that this step improves our ability to identify clinically relevant metabolic changes. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
    Human Brain Mapping 03/2014; 35(3). DOI:10.1002/hbm.22229 · 6.92 Impact Factor
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    ABSTRACT: Pathological abnormalities including demyelination and neuronal loss are reported in the outer cortex in multiple sclerosis (MS). We investigated for in vivo evidence of outer cortical abnormalities by measuring the magnetisation transfer ratio (MTR) in MS patients of different subgroups. Forty-four relapsing-remitting (RR) (mean age 41.9 years, median Expanded Disability Status Scale (EDSS) 2.0), 25 secondary progressive (SP) (54.1 years, EDSS 6.5) and 19 primary progressive (PP) (53.1 years, EDSS 6.0) MS patients and 35 healthy control subjects (mean age 39.2 years) were studied. Three-dimensional (3D) 1×1×1mm(3) T1-weighted images and MTR data were acquired. The cortex was segmented, then subdivided into outer and inner bands, and MTR values were calculated for each band. In a pairwise analysis, mean outer cortical MTR was lower than mean inner cortical MTR in all MS groups and controls (p<0.001). Compared with controls, outer cortical MTR was decreased in SPMS (p<0.001) and RRMS (p<0.01), but not PPMS. Outer cortical MTR was lower in SPMS than PPMS (p<0.01) and RRMS (p<0.01). Lower outer than inner cortical MTR in healthy controls may reflect differences in myelin content. The lowest outer cortical MTR was seen in SPMS and is consistent with more extensive outer cortical (including subpial) pathology, such as demyelination and neuronal loss, as observed in post-mortem studies of SPMS patients.
    Multiple Sclerosis 02/2014; 20(10). DOI:10.1177/1352458514522537 · 4.86 Impact Factor

Publication Stats

10k Citations
1,549.14 Total Impact Points


  • 2014
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 2013–2014
    • University of Otago
      • Department of Medicine (Dunedin)
      Taieri, Otago, New Zealand
  • 2009–2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 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
  • 2002–2012
    • London Research Institute
      Londinium, England, United Kingdom
    • Otto-von-Guericke-Universität Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 2011
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
    • University College London Hospitals NHS Foundation Trust
      • Department of Neurosurgery (National Hospital for Neurology and Neurosurgery)
      Londinium, England, United Kingdom
  • 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