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Spinal cord pathology can be functionally very important in neurological disease. Pathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases, although the clinical relevance of abnormalities detected histopathologically is difficult to assess without a reliable way to assess cord GM and WM in vivo. In this study, the feasibility of GM and WM segmentation was investigated in the upper cervical spinal cord of 10 healthy subjects, using high-resolution images acquired with a commercially available 3D gradient-echo pulse sequence at 3T. For each healthy subject, tissue-specific (i.e. WM and GM) cross-sectional areas were segmented and total volumes calculated from a 15 mm section acquired at the level of C2-3 intervertebral disc and magnetisation transfer ratio (MTR) values within the extracted volumes were also determined, as an example of GM and WM quantitative measurements in the cervical cord. Mean (± SD) total cord cross-sectional area (TCA) and total cord volume (TCV) of the section studied across 10 healthy subjects were 86.9 (± 7.7) mm(2) and 1302.8 (± 115) mm(3), respectively; mean (±SD) total GM cross-sectional area (TGMA) and total GM volume (TGMV) were 14.6 (± 1.1) mm(2) and 218.3 (± 16.8) mm(3), respectively; mean (± SD) GM volume fraction (GMVF) was 0.17 (± 0.01); mean (± SD) MTR of the total WM volume (WM-MTR) was 51.4 (± 1.5) and mean (± SD) MTR of the total GM volume (GM-MTR) was 49.7 (± 1.6). The mean scan-rescan, intra- and inter-observer % coefficient of variation for measuring the TCA were 0.7%, 0.5% and 0.5% and for measuring the TGMA were 6.5%, 5.4% and 12.7%. The difference between WM-MTR and GM-MTR was found to be statistically significant (p=0.00006). This study has shown that GM and WM segmentation in the cervical cord is possible and the MR imaging protocol and analysis method presented here in healthy controls can be potentially extended to study the cervical cord in disease states, with the option to explore further quantitative measurements alongside MTR.

The possibility of quantifying the superimposed signal of glutamate and glutamine (Glx) and its components by ¹H magnetic resonance spectroscopy (MRS) in the spinal cord is an exciting challenge with important clinical applications in neurological conditions. The spinal cord is a particularly difficult region of interest due to its small volume, magnetic field inhomogeneities and physiological motion. In this study, we investigated for the first time the feasibility of obtaining quantitative measurements of Glx in healthy cervical spinal cord by ¹H MRS at 3 T. The aim of this study was to compare two commercially available MRS sequences by spectral simulations and in vivo. A short echo time (TE) point resolved spectroscopy (PRESS) with TE = 30 ms and a stimulated echo acquisition mode (STEAM) with TE = 11 ms and mixing time (TM) = 17 ms were compared for reliability of Glx fit. Data allowed us to determine sample size estimates for future clinical studies for the first time. Results showed that PRESS provided a reliable fit for Glx in all cases (Cramér Rao lower bounds20%) whereas no reliable Glx fits were achieved using STEAM. Neither protocol provided reliable Glu quantification. The power calculations showed that a minimum sample size of 17 subjects per group was needed to detect Glx changes of20% using the PRESS sequence. This study proposed a clinically feasible MRS method for Glx detection in the human cervical cord in vivo including sample sizes needed for conclusive clinical studies.

To identify an improved method for measuring spinal cord cross-sectional area (CSA) using magnetic resonance imaging (MRI) in multiple sclerosis (MS).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.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.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.

In MRI studies of multiple sclerosis (MS), brain grey matter (GM) and spinal cord atrophy correlate with disability.1 2 However, it is uncertain whether they independently associate with long-term disability. We measured upper cervical cord cross-sectional area (UCCA) in a cohort of patients ∼20 years after presenting with a clinically isolated syndrome (CIS) suggestive of MS. Associations of brain GM atrophy and white matter (WM) lesion load with disability had been previously observed in the cohort.1 We now report UCCA measurements and independent associations of the cord and brain measures with disability. Seventy patients presenting with CIS had analysable brain and MRI scans acquired on a 1.5 T scanner after a median of 20 years (range 18–27). Clinically definite MS (CDMS) was diagnosed clinically.3 Disability was assessed with the expanded disability status scale (EDSS)4 and MS functional composite score (MSFC) plus its three components, paced serial auditory attention test (PASAT; 3 s interval), nine-hole peg test (9HPT) and 25-foot timed walk (T25FW). CDMS subgroups were defined as relapsing–remitting (RR) or secondary progressive (SP) MS; those with an EDSS ≤3 were classified as benign.5 At the 20-year follow-up, 27 remained CIS, 32 had RRMS (21 benign MS, 11 non-benign RRMS (EDSS>3)), and 11 had SPMS. UCCA and brain MR parameters were measured as previously described.1 2 UCCA was also measured in 17 healthy volunteers. Statistical analysis was performed using the SPSS Version 11.0 (SPSS, Chicago, Illinois) and Stata 9.2 (Stata Corporation, College Station, Texas). Subgroup comparisons of UCCA were performed …

Purpose: To investigate the three-dimensional (3D) fast-recovery fast spin-echo accelerated (FRFSE-XL) sequence as a new application for measuring the intraorbital optic nerve (ION) mean cross-sectional area in vivo and to determine its value within a commonly used high resolution imaging protocol.Materials and Methods: The entire ION was scanned in nine healthy volunteers (mean age 32 +/- 4 years) using the 3D FRFSE-XL sequence and a commonly used high resolution short-echo fast fluid-attenuated inversion-recovery (sTE fFLAIR) sequence with identical slice locations at 1.5T. The mean cross-sectional area from both sequences was measured on a slice-by-slice basis from 3 mm behind the globe to the orbital apex. The reproducibility of both techniques was assessed from repeated scans (scan-rescan) and repeated image analysis (intraobserver).Results: Measurement of the mean cross-sectional area of the anterior 9 mm segment of the ION was only possible using the 3D FRFSE-XL sequence with a mean area of 11.6 +/- 2.2 mm(2) (scan rescan COV = 3.3 +/- 1.5, intraobserver COV = 2.4 +/- 0.02) whereas the remainder segment of the ION (i.e., 9 mm behind the globe to the orbital apex) could only be measured with the use of the sTE fFLAIR with a mean area of 8.5 +/- 1.7 mm(2) (scan rescan COV = 4.9 +/- 2.5 and intraobserver COV = 3.70 +/- 0.03).Conclusion: The 3D FRFSE-XL allows fast and reproducible measurement of the cross-sectional area of the anterior 9mm segment of the ION, which is not possible using commonly used imaging sequences due to image degradation from motion, and is of complementary value to the existing imaging protocol for ION atrophy quantification.

Background 1.5Tesla 1H-magnetic resonance spectroscopy (MRS) demonstrates reduced spinal cord (SC) N-acetyl-aspartate (NAA) following SC relapses in MS but it remains unknown whether glutamate-glutamine (Glx) metabolism is also affected, as in the brain. Using 3Tesla MRS, we quantified Glx following SC relapse and assessed the clinical relevance of metabolite changes. Methods SC metabolites were quantified in 20 RRMS patients (14F; mean age 41 yrs.) within 4 weeks of cervical SC relapse and 22 controls (17F; mean age 44 yrs.) using a cardiac-gated PRESS sequence; TE=30 ms; MOIST water suppression on a 3T Philips scanner. MSFC and EDSS scores were obtained for patients. Results SC NAA was reduced (p=0.023) and Glx was elevated (p=0.036) compared to controls. In patients, higher EDSS scores were independently predicted by higher creatine (p=0.032) and choline (p=0.041) and longer timed walk was independently predicted by higher creatine (p=0.002), myoinositol (p=0.025) and choline (p=0.044). Conclusions Higher choline, creatine and myoinositol are associated with disability and may reflect important pathological processes. Elevated Glx wasn9t predictive of disability but may cause excitotoxicity and hinder recovery; longitudinal study is therefore needed.

Purpose.: To present a new acquisition and analysis protocol for reliable and reproducible segmentation of the entire intraorbital optic nerve (ION) mean cross-sectional area by means of magnetic resonance imaging (MRI) at 3 tesla (T). / Methods.: Eight healthy volunteers (mean age 31, five were male) gave written informed consent and both of their IONs were imaged individually using a coronal-oblique T2-weighted fast multidynamic image acquisition scheme; the proposed acquisition scheme has its rationale in combining separately acquired volumes and registering them to account for motion-related artifacts commonly associated with longer acquisitions. Mean cross-sectional area of each ION was measured using a semiautomated image analysis protocol that was based on an active surface model previously described and used for spinal cord imaging. Reproducibility was assessed for repeated scans (scan-rescan) and repeated image analysis performance (intraobserver). / Results.: Mean and SD values of the left ION cross-sectional area for the eight healthy volunteers were 5.0 (±0.7) mm2 and for the right ION were 5.3 (±0.8) mm2. Mean scan-rescan coefficient of variation (COV) for the left ION was 4.3% and for the right was 4.4%. Mean intraobserver COV for the left ION was 2.1% and for the right was 1.8%. / Conclusions.: This study presents a new MRI acquisition and analysis protocol for reliable and reproducible in vivo measurement of the entire ION mean cross-sectional area as demonstrated in a pilot study of healthy subjects. The protocol presented here can be used in future studies of the ION in disease state.

Objective: To classify spinal cord lesions in multiple sclerosis (MS) based on white matter (WM) columns, and grey matter (GM) and WM involvement using magnetic resonance imaging (MRI). Background The localization of spinal cord lesions has not been well documented on MRI, although morphology and distribution of plaques have been characterized in post-mortem studies. Design/Methods: MRI was performed on the cervical cord in 16 MS patients (10 female, mean age 44.8) (8 relapsing remitting (RR) MS, 7 secondary progressive (SP) MS, 1 clinically isolated syndrome (CIS)). Axial phase sensitive inversion recovery (PSIR) and gradient-echo sequences were acquired. Two readers reviewed both images simultaneously and reached a consensus about classification of lesions by location: anterior (AC), lateral (LC) or posterior columns (PC). A sub-classification of lesions in mixed WM/GM and those involving WM only was also performed. Lesions were outlined manually on PSIR images and compared with mean cord area. Results: 51 lesions were identified, 24 in RRMS, 22 in SPMS, 5 in CIS. Three lesions were seen in AC (5.8%), 18 in PC (35.3%) and 30 in LC (58.9%). 33% of lesions involved WM alone and 67% involved both GM and WM; no pure GM lesions were identified. Mean lesion area in AC was 4.3mm2, LC 8.5mm2, PC 11.3mm2, with lesions in each column covering 6.1%, 12% and 16.1% of mean cord area respectively, mean lesion length in AC 18.3mm, LC 17.6mm and PC 24.8mm. Conclusions: Most lesions seen involved GM and WM, and were in the PC and LC, in agreement with post-mortem studies. However, no pure GM lesions were seen, suggesting technical limitations or a difference in patient characteristics from post-mortem studies. MRI may permit classification of spinal cord lesion location, area and length, which maybe correlated in future with disability to provide new insights into their functional effects. Supported by: MS Society. Disclosure: Dr. Kearney has nothing to disclose. Dr. Miszkiel has received research support from Biogen Idec and GlaxoSmithKline, Inc. Dr. Yiannakas has nothing to disclose. Dr. Ciccarelli has nothing to disclose. Dr. Miller has received personal compensation for activities with UCL Institute of Neurology, Biogen Idec, GlaxoSmithKline, and Bayer Schering Pharma. Dr. Miller has received personal compensation in an editorial capacity for Journal of Neurology. Dr. Miller has received research support from GlaxoSmithKline, Biogen Idec, and Novartis.

MRI; Multi-echo QSM; Quantitative susceptibility mapping Imágen por resonancia magnética; QSM de ecos múltiples; Mapeo cuantitativo de susceptibilidad Imatge per ressonància magnètica; QSM de ressò múltiple; Mapeig quantitatiu de susceptibilitat Purpose To compare different multi-echo combination methods for MRI QSM. Given the current lack of consensus, we aimed to elucidate how to optimally combine multi-echo gradient-recalled echo signal phase information, either before or after applying Laplacian-base methods (LBMs) for phase unwrapping or background field removal. Methods Multi-echo gradient-recalled echo data were simulated in a numerical head phantom, and multi-echo gradient-recalled echo images were acquired at 3 Tesla in 10 healthy volunteers. To enable image-based estimation of gradient-recalled echo signal noise, 5 volunteers were scanned twice in the same session without repositioning. Five QSM processing pipelines were designed: 1 applied nonlinear phase fitting over TEs before LBMs; 2 applied LBMs to the TE-dependent phase and then combined multiple TEs via either TE-weighted or SNR-weighted averaging; and 2 calculated TE-dependent susceptibility maps via either multi-step or single-step QSM and then combined multiple TEs via magnitude-weighted averaging. Results from different pipelines were compared using visual inspection; summary statistics of susceptibility in deep gray matter, white matter, and venous regions; phase noise maps (error propagation theory); and, in the healthy volunteers, regional fixed bias analysis (Bland–Altman) and regional differences between the means (nonparametric tests). Results Nonlinearly fitting the multi-echo phase over TEs before applying LBMs provided the highest regional accuracy of and the lowest phase noise propagation compared to averaging the LBM-processed TE-dependent phase. This result was especially pertinent in high-susceptibility venous regions. Conclusion For multi-echo QSM, we recommend combining the signal phase by nonlinear fitting before applying LBMs. Supported by the UK Engineering and Physical Sciences Research Council (EPSRC), award number: 1489882 (e.b.); by the EPSRC-funded UCL Centre for Doctoral Training in Medical Imaging, grant EP/L016478/1 (a.k.), and the Department of Health's National Institute for Health Research funded Biomedical Research Centre at University College London Hospitals (a.k.); by the UCL Leonard Wolfson Experimental Neurology Centre, grant PR/ylr/18575 (d.l.t) The Queen Square MS Centre, where part of the MRI scans for this work were performed, is supported by grants from the UK MS Society and by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (UCLH/BRC). F. Grussu was supported by PREdICT, a study at the Vall d'Hebron Institute of Oncology in Barcelona funded by AstraZeneca (f.g.), and funding from the postdoctoral fellowships program Beatriu de Pinós (2020 BP 00117), funded by the Secretary of Universities and Research, Government of Catalonia (f.g.)

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.