ACTRIMS-ECTRIMS MSBoston 2014: Poster Sessions 2

<span title="">2014</span> <i title="SAGE Publications"> <a target="_blank" rel="noopener" href="" style="color: black;">Multiple Sclerosis</a> </i> &nbsp;
Natalizumab, a monoclonal antibody targeting a4b1, is considered to be a highly effective therapy in RRMS. The efficacy of NTZ is related to its profound effect on reducing lymphocyte trafficking into the CNS. However, its effect on tissue injury in the CNS and axonal metabolic function is not well understood. Objectives: To determine the effect of natalizumab (NTZ) on brain tissue injury and cervical cord volume in a multi-modal advanced MRI study. Methods: A four-year, prospective, open-label
more &raquo; ... study was conducted in RRMS patients initiating therapy with NTZ, who were previously naïve to NTZ therapy. Multi-modal advanced brain MRI including 3D-T1W, DTI, MTR, multi-voxel 1 H-MRS, and cervical cord MRI were obtained at baseline and annually thereafter. Focal pathology in the brain was also tracked longitudinally by following 3 to 5 lesions per brain. Age-matched healthy controls (HC) were also imaged annually. We are presenting the twoyear interim analysis of this ongoing four-year study. Results: Twenty-five patients with RRMS initiating therapy with NTZ participated. At year 2 mean tNAA/tCr improved from 1.98 to 2.10 (p=0.003). Compared to baseline and HC, there was no significant loss of cortical surface volume or thalamic volume at year 2. Focal T2 lesion pathology followed longitudinally (102 non-enhancing lesions) showed mean MTR improve from 44.37% to 46.16% (p=0.0006); mean FA from 0.247 to 0.290 (p=0.001); voxel-wise MTR showed 88.4% of the lesions to be stable over 2 years. T2 lesion volume and T1 lesion volume were significantly reduced. Brain volume change (PBVC) was -0.81% from baseline to year 1 and -0.53% from year 1 to year 2. Cervical cord crosssectional area (CSA) measured at C2 level changed from 75.76 mm 2 to 74.45 mm 2 (p=0.16). There was no significant different when comparing the net change in HC. Conclusions: This study demonstrates the effect of NTZ on preserving axonal metabolic function, as well as improving focal pathology indicated by improving MTR and FA. There was no significant loss of thalamic or cortical surface volume, when comparing to HC. These results indicate that besides a profound effect of NTZ at the blood-brain barrier level, there may be additional effects on tissue injury and axonal metabolic function in the CNS. Further longitudinal follow-up with annual MRI scans is ongoing to investigate the anti-inflammatory and potential neuroprotective effects of NTZ in the CNS. P492 Corpus callosal myelin water fraction and transcallosal inhibition in multiple sclerosis IM Background: Magnetic resonance imaging (MRI) techniques assessing T 2 relaxation can measure myelin water fraction (MWF), a marker for central nervous system demyelination in multiple sclerosis (MS). Transcallosal inhibition (TCI), elicited by transcranial magnetic stimulation (TMS), reflects functional integrity of fibres in the corpus callosum (CC). Objectives: To characterize the relationship between MWF in the CC and TCI assessed by TMS-evoked potentials in MS subjects on glatiramer acetate. This relationship may guide the use of MWF for evaluating therapies that induce remyelination or have neuroprotective effects, and improve the design of clinical trials for more efficient development of new treatments. Methods: Twenty-six relapsing-remitting MS patients (5M/21F, mean age 42.3: range 28-59y, EDSS range 1.0-6.0, disease duration range 1-35y) and 10 controls (2M/8F, mean age 43.4y) underwent both MRI and TMS testing. The MRI protocol included a 32 echo T 2 relaxation GRASE sequence (TR=1000 ms, 10 ms echo spacing, 20-5 mm slices). The T 2 signal was modelled via multiple exponential components and the MWF was computed as the ratio of the short T 2 component to the total area. The CC was segmented anteroposteriorly into five regions and mean MWF was calculated for each. TMS was performed using a figure-of-eight coil delivering focal stimulation over the primary motor cortex representation of the forearm extensor musculature. Single pulses were delivered ipsilaterally to elicit a transient suppression in the electromyographic activity of the forearm during a voluntary isometric grip contraction (50% max). The onset latency, duration and depth of this suppression were used to quantify levels of TCI. Results: TCI duration was significantly longer in MS subjects (36.0 ± 5.2 ms) than in controls (25.6 ± 8.2 ms, p = 0.016). MWF was 35% higher in the posterior than in the anterior CC (p< 0.0001). Median MWF was lower in MS subjects in all five regions, though without statistical significance. In MS subjects, the log transformed TCI depth was negatively correlated with the MWF of the posterior CC midbody (r = -0.73, p = 0.039), a region previously shown to be critical in TCI transmission. Poster session 2, 20 (s1) Multiple Sclerosis Journal 2014; 20: (S1) 285-496 Conclusions: The relationship between MWF in the CC and TCI assessed by TMS-evoked potentials in MS subjects improve understanding of the structure and function of myelin in MS. MWF and TMS measures may provide biomarkers of demyelination and disease progression. P493 White matter and long-tract lesions play a marginal role in determining cortical atrophy Background: To what extent retrograde axonal degeneration induces cortical atrophy in white matter diseases is still debated. Neuroimaging studies of the sensory-motor cortex in patients with severe tract pathology, such as traumatic spinal cord injury (SCI) and neuromyelitis optica (NMO) with extensive spinal cord lesions, gave conflicting results. Objectives: To analyse cortical atrophy in patients with severe lesions of the sensory-motor tracts (SCI and NMO), inflammatory tumour-like lesions (TLL) and relapsing remitting multiple sclerosis (RRMS) with or without spinal cord lesions. Methods: Fifteen patients with severe SCI (mean follow-up period: 5.8 years), 10 patients affected from NMO with extensive inflammatory spinal cord lesions (mean disease duration: 6.2 years), 5 patients with TLL and 30 patients with MS (15 with and 15 without spinal cord lesions) were included in the study. MRI examination included T2, 3D T1, FLAIR, double inversion recovery (DIR) and diffusion tensor imaging (DTI) sequences. Cortical atrophy was analysed by Freesurfer. Results: A significant thinning of sensory-motor cortex, unrelated to subcortical T2 lesion load and the presence of spinal cord lesions, was observed in RRMS (p< 0.001), while it was modest in SCI (p ranging from 0.08 to < 0.01) and NMO (p ranging from 0.04 to 0.02). Global and regional cortical thickness was significantly decreased in RRMS compared to both NMO and SCI (p< 0.001 for all comparisons). In TLL, cortical atrophy was modest in the cortex over the lesions compared to that of the contralateral hemisphere (p=0.02). Fractional anisotropy was significantly decreased in the cortex of RRMS while it was normal in SCI, NMO, and TTL. Conclusions: Whether cortical atrophy in MS is the results of retrograde axonal degeneration or is mainly related to a direct (local) damage is still debated. We found that severe long-trait damage induces only a modest cortical thinning in the sensory-motor cortex, while in RRMS cortical atrophy was relevant even in patients without spinal cord lesions and with low T2 lesion load. Thus, retrograde degeneration of axons seems to plays only a marginal role in determining cortical thinning in MS. A role for a local pathological process, determining neuron loss and cortical atrophy, is also supported by the finding that FA of the cortex was normal in SCI, NMO and TLL, and significantly decreased in RRMS. P494 Characteristic of orbit magnetic resonance imaging in neuromyelitis optica and multiple sclerosis patients presenting with optic neuritis Background: Patients with neuromyelitis optica (NMO) and multiple sclerosis (MS) both can present with optic neuritis (ON). There have been several reports on neuroimaging findings of ON in NMO and MS, but the results have been contradictory. Previous studies reported patients with chiasmal involvement developed clinically definite MS, whereas recent studies suggested there was a trend toward more posterior location within the anterior visual pathways in NMO-associated ON. Objectives: We aimed to determine whether there were magnetic resonance imaging (MRI) characteristics of the anterior visual pathways in acute ON to distinguish NMO/NMO spectrum disorders (NMOSD) from MS. Methods: We included 26 NMO/NMOSD patients (34 affected eyes) and 48 MS patients (71 affected eyes) who presented with ON. The NMO/NMOSD patients fulfilled the revised diagnostic criteria and showed seropositivity for NMO-IgG. MS patients met 2010 McDonald diagnostic criteria. We analyzed orbit MRIs obtained within 60 days of ON onset. The MRI parameters assessed were as follows: extent and location of affected optic pathway (retrobulbar, canalicular, intracranial, optic chiasm, and optic tract) , severity of optic nerve swelling and enhancement, and presence of involvement of adjacent brain structures such as hypothalamus. Results: The female percentage was 84.6% in the NMO/NMOSD group and 79% in the MS group. The mean age (SD) was 36 years (13.6) and 39 years (13.9) in NMO/NMOSD patients and MS patients, respectively. The number of patients with chiasmal involvement was significantly higher in the NMO/NMOSD group (n=8, 20.0%) than in the MS group (n=3, 3.8%) (p=0.006). The optic tract was more frequently affected in NMO/NMOSD patients (n=4, 10.0%) than in MS patients (n=1, 1.3%) (p=0.042). NMOassociated ON have more extensive lesion beyond the three segments of optic pathway. Hypothalamic involvement was exclusively seen in NMO-associated ON (n=3, p=0.035). There were no significant differences in the severity of swelling and enhancement. Conclusions: Based on our results, NMO/NMOSD-associated ON shows more extensive lesions than MS-associated ON and involves more posterior parts within the anterior visual pathways. Concurrent involvement of hypothalamus is a unique feature in NMO/NMOSD-associated ON. These findings may be related to the distribution of sites of high AQP4 expression and help to distinguish ON in NMO/NMOSD from MS. P495 High field spinal cord imaging in multiple sclerosis at 7 Tesla Background: Spinal cord is a major site of involvement in progressive MS. Imaging of the spinal cord is challenging due to its small size and location in a bony canal. Conventional MRI does not detect the diffuse damage occurring in grey matter and normal appearing white matter. Poster session 2, 20 (s1) Objectives: Our purpose is to evaluate the sensitivity of 7T to detect SC lesions in MS patients compared to lower field (3T), clinically standard MRI evaluation. We also show the improvement in gray (GM) and white matter (WM) visibility allows for a discrimination of GM lesions, which are known to exist from histopathological studies, but have not been shown at 3T. Methods: MR scans were performed at 7T (Philips Healthcare) with a novel 16-channel cervical spinal cord receive coil. High resolution T1-and T2*-weighted scans were acquired at 0.5x0.5x5mm3 resolution in 9 minutes with the following parameters: T1 -3D FFE, TR/TE/flip angle = 30ms/4ms/60°, T2*weighted -multi-slice FFE, TR/TE/flip angle = 305ms/9ms/25°. Conventional T2*-weighted turbo spin echo scans were obtained in the same patients at 3T using a standard clinical protocol. 7T scans were obtained in 15 healthy controls and 23 MS patients. The SNR and CNR were calculated. Results: We were able to obtain T1, T2*, PD weighted axial sequences, as well as T2 w sagittal sequences, in under 15 minutes. On the other hand, the high SNR of 7T allows us to aim for high in-plane resolutions. While clinical resolution scans can be performed in 2 minutes, we were able to get twice the clinical resolution, 0.5 x 0.5 mm, in a 3 minute scan.WM SNR and WM-Lesion CNR were 2.1 and 1.8 times higher at 7T compared to 3T. In sagittal T2 scans, 4.5 +/-1.5 lesions were detected at 7T compared to 2.5 +/-2.2 at 3T. Spinal cord cross sectional area at C2/3 space was 75.34 +/-9.36 sq mm in MS patients, compared to 83.87 +/-4.87 sq mm in healthy controls. Conclusions: In this first ever report of 7T MRI in large numbers of MS patients, we show significant gains in in-plane resolution (more accurate determination of cord atrophy) and lesion detection. Due to the higher SNR and CNR afforded at 7T, evaluation of the SC in MS shows a significant improvement in lesion visualization compared to the clinical standard at 3T. Finally, 7T SC MRI allows for more accurate assessment of the magnitude and extent of SC involvement in patients with MS, which may provide greater confidence in diagnosis and treatment monitoring. Background: Upper cervical cord area (UCCA) is strongly associated with physical disability in MS patients, particularly in advanced stages of disease. Many sites do not routinely acquire MRI that can provide reliable measures of UCCA. We performed a 3T MRI study using standard brain high-resolution 3D T1-weighted (T1W) volumes that included the upper cervical cord to provide estimates of UCCA. Objectives: To compare the multi-site utility of UCCA determined from brain T1W MRI to direct spinal cord MRI-obtained UCCA in patients with MS. Methods: Brain MPRAGE sequences (sagittal 1mm isotropic voxels) were acquired at the Brigham Women's Hospital (BWH, n=12) and UCSF (n=68), as part of the SUMMIT consortium. Both sites used the same Siemens Skyra 3T MRI, 20-channel head and neck coil, and pulse sequence. UCCA was determined using JIM software, independently at the 2 sites. UCCA was compared within each site with spinal cord specific sequences (T2W images at BWH and PSIR at UCSF). A subset at UCSF (n=12) was matched for sex, EDSS, and disease duration for comparison of MPRAGE-derived UCCAs and correlation with disability to evaluate multi-center data integration. Results: BWH: N=12, 8 females, mean (SD): 17 (15) years disease duration, 3.0 (2.1) EDSS, 10 RRMS, 1 SPMS, 1 PPMS. UCSF: N=68, 44 females, 17 (11) years disease duration, 2.9 (1.8) EDSS, 50 RRMS, 15 SPMS, 3 PPMS. Brain MPRAGE UCCA were BWH: 72(7) mm2 and UCSF: 71(10) mm2. Strong correlations were found between the UCCA from MPRAGE and spinal cord specific sequences (Pearson BWH R2=0.63, UCSF R2=0.96). Correlation coefficients for EDSS predicted by UCCA from MPRAGE were BWH: Spearman r=-0.74 p=0.006; Pearson r=-0.66, -0.90: -0.14 CI and in the matched UCSF cohort: r=-0.73, p=0.007; Pearson r=-0.64, -0.89: -0.11 CI. Combining the datasets we found (N=24) Spearman r= -0.69, p<0.001; Pearson r=-0.63, -0.83: -0.31 CI). The correlations from the cord specific sequences were similar or lower. Statistical power (alpha=0.05) for the combined MPRAGE-UCCA data was 0.96 for N=24 while power for the individual sites were 0.71 and 0.67 for N=12 and predicted power at N=24 was 0.96 and 0.95. Conclusions: Across sites, concordant UCCA values and correlations with EDSS were found. No loss of power due to combining data was observed. Such data potentially provide readily accessible UCCA estimates for integration in large multi-site trials and can provide an estimate of spinal cord atrophy without direct cord images. P497 Identification of tissue-specific MRI markers to assess protection and repair in response to fingolimod Background: While the immunological effects of Fingolimod are well established, there is controversy regarding its role in promoting tissue repair. Advanced MRI techniques such as diffusion tensor (DTI) and diffusional kurtosis imaging (DKI) provide information about tissue microstructure. Using DKI, and a diffusion model of white matter (WM) is possible to derive indices of axonal degeneration (axonal water fraction) and de and re-myelination (tortuosity). Objectives: Using a combined DKI and histological analysis to assess the impact of Fingolimod on WM and GM brain tissue repair in experimental models with minimal immunological component: Lysolecithin-induced de-and re-myelination and AdIl-1induced GM injury. Poster session 2, 20 (s1) Multiple Sclerosis Journal 2014; 20: (S1) 285-496 Methods: WM demyelination was induced by stereotaxic injection of 1% lysolecithin into the corpus callosum (n=4 treated with Fingolimod (3mg/kg); n=4 treated with vehicle and n=4 controls injected with PBS). GM lesions were induced by stereotaxic injection of AdIL1 into the cortex (n=4 treated with Fingolimod; n=4 treated with vehicle). In-vivo brain MRI was performed on a 7.0 Tesla Bruker scanner. DKI data were acquired using EPI sequence with 30 gradient directions (b-values: 1.25 and 2.5ms/ µm^2) at 7, 14 and 28dpi for lysolecithin-injected mice and 7, 14 and 21-dpi for AdIL1-injected mice. After MRI, mice were perfused with 4% PFA and brains were processed for cryostat embedding. 20µm sections were immunostained using standard protocols. Primary antibodies were used at 1:200 for Olig2 and CD11b. GFAP was used at 1:500. Samples were examined with a Leica Microsystems confocal microscope. Results: At 7 dpi, ROI analysis showed no significant changes in WM integrity parameters in lysolecithin-injected mice treated with Fingolimod compared to PBS-injected control mice. Significant changes were observed in AdIl-1 injected mice when compared to control PBS-injected mice (p< 004). Immunohistochemistry showed an increase of Olig2+, Cd11b, and GFAP cells in lysolecithin-injected brains at 7dpi whereas a decrease in all these cell types and in NeuN was detected in AdIL-1-injected brains. Conclusions: Our preliminary results suggest that Fingolimod might exert a protective effect thus reducing the severity of tissue brain damage 7 dpi after injections of lysolecithin or AdIL-1 P498 Spinal cord and brain atrophy in neuromyelitis optica: a comparative study with MS and healthy controls Background: Both spinal cord and brain atrophy in neuromyelitis optica (NMO) was reported. However how is the relationship between brain and spinal cord pathology in NMO compared with MS, and which one can sever as a biomarker for correlating with clinical disability and for clinical trials is unclear. Objectives: To investigate the spinal cord and brain volume in NMO, and its relationship with other MRI measurements and clinical disability, compared with well-matched multiple sclerosis (MS) patients and healthy controls (HC). Methods: We recruited 35 NMO patients, 35 MS patients and 35 healthy controls (HC) with both spinal cord and brain images at 3 Tesla MRI. Mean upper cervical cord cross-sectional area (MUCCA), brain parenchymal (BPF), grey (GMF) and white matter fraction (WMF), spinal cord and brain lesion loads were measured and compared among groups. Multivariate associations between spinal cord and brain volume measurement and clinical variables were assessed by partial correlation and multiple linear regression model. Results: Both NMO (0.73±0.08cm 2 ) and MS (0.75±0.09 cm 2 ) showed smaller MUCCA than HC (0.79±0.07 cm 2 ) (p< 0.001), while no significant difference was identified between MS and NMO. The NMO patients showed lower BPF and WMF than HC, however with no significant difference in GMF. MS patients had lower BPF and GMF than NMO patients. MUCCA was correlated with total lesion length (r=-0.55, p=0.001), a higher number of relapses (r=-0.435, p=0.011) and EDSS (r=-0.75, p< 0.001) in NMO, while in MS MUCCA was correlated with WMF (r=0.450, p=0.009) and EDSS (r=-0.438, p=0.011). MUCCA was the only independent variable for predicting clinical disability measured by EDSS in NMO (R 2 =0.22, p< 0.001) and MS (R 2 =0.16 p=0.019). Conclusions: NMO showed predominately spinal cord atrophy with mild brain atrophy mainly in WM, while MS demonstrated much more severe brain atrophy especially in GM. MUCCA is the essential MRI-derived parameter for explaining clinical disability in NMO and MS, and may serve as a potential biomarker for further clinical trials especially in NMO. P499 MR frequency shift imaging as a sensitive measure of longitudinal changes in multiple sclerosis lesions Background: Multiple sclerosis (MS) is characterized by the appearance of focal and diffuse lesions in the brain and spinal cord due to demyelination, episodic inflammation and axonal damage. Magnetic resonance (MR) frequency images contain quantitative information related to tissue magnetic susceptibility and microstructure. Objectives: As shown in a previous serial study (Wiggermann et al., Neurology 81, 2013), MR frequency increases sharply when new lesions appear and remains elevated for at least 6 months. Here, we present long-term follow up (LTF) data from the previous short-term study cohort. We hypothesize lesions will demonstrate a reduction in the MR frequency signal due to axonal destruction and axonal loss, in agreement with theoretical predictions. Methods: 8 subjects with relapsing-remitting MS (at LTF: mean age=44.5yr (range: 34-57yr), median EDSS=2.5 (range: 1-4.5), mean disease duration=15.4yr (range: 7-30yr)) were scanned monthly over 6 months and received one LTF scan after 3.2-5.6 years on a 3T Philips Achieva system. 3 healthy controls (age=38-48yr) were scanned at months 0, 6 and LTF. FLAIR (Fluid Attenuated Inversion Recovery) and Gd-enhanced T 1 w images were acquired for lesion detection. Frequency shift images were acquired using a 3D single Gradient Echo sequence (FOV=240x166x64mm 3 ,voxel size =0.43x0.43x1mm 3 , TR/TE=40/20ms) and registered using FSL´s FLIRT. Regions of Interest were manually defined on MR frequency images for enhancing lesions, normal-appearing white matter (NAWM) and normal WM (NWM) in controls. Statistical analysis was performed using a linear mixed effect model. Poster session 2, 20 (s1) 289 Multiple Sclerosis Journal 2014; 20: (S1) 285-496 Results: Visually, new MS lesions seen at months 0-6 nearly disappeared on MR frequency shift images at LTF. After the initial frequency increase at month 0-6, the frequency decreased over time while control regions remained constant (NAWM in subjects, p=0.3; and NWM in controls, p=0.8). The decrease in frequency of new lesions at LTF was significant compared to months 2-6, which showed elevated frequency shortly after first appearance (p=0.004). Conclusions: Our data is in good agreement with theoretical predictions (Yablonskiy et al., PNAS 109, 2012) of frequency shifts in MS lesions. The preliminary results demonstrate the sensitivity of frequency shifts to measure microstructural changes in MS lesions at high spatial resolution, which occur due to the destruction of the myelin sheath and axonal damage. Remyelination could also explain the observed decrease in frequency at longterm follow up. P500 Distinction between neuromyelitis optica and multiple sclerosis using multi-voxel pattern classification Background: Current magnetic resonance imaging (MRI) criteria to support the diagnosis of multiple sclerosis (MS) are based on dissemination in time (DIT) and space (DIS) of central nervous system (CNS) white matter lesions (WML). However, application of these criteria is not always straightforward and may delay diagnosis in patients who do not develop the required number of WML. An alternative approach to support a diagnosis of MS using MRI may be to detect a histological feature characteristic of MS in vivo. One such feature, the ´central vein´ in WML, has become accessible through application of T 2 * based techniques. FLAIR* is a postprocessing algorithm combining T 2 * with an established sequence for WML detection -fluid attenuated inversion recovery (FLAIR). Objectives: To explore whether FLAIR* could be superior to current MRI DIS/DIT criteria with respect to making a diagnosis of MS using MRI datasets acquired at a single time point and at a standard MRI field strength (3T). Poster session 2, 20 (s1) Multiple Sclerosis Journal 2014; 20: (S1) 285-496 Methods: Seventeen people (11 men; age 39± 8.6 years; disease duration 7± 5.3 years) with relapsing MS (pwRMS) had MRI using a 3T system to acquire 3D FLAIR (after Gadolinium injection) 3D T 2 and T 2 *. FLAIR* images were constructed using MIPAV ( and JIST ( image processing software. FLAIR* images were assessed by two observers independently, unaware of patients´ clinical information. WML >3mm were identified, their location and the presence of a central hypointensity suggestive of a vein (central vein sign; CVS) recorded. The proportion of CVS positive (CVS+) WML was calculated for each patient. A proportion of >40% CVS+ WML was considered diagnostic for MS. The McNemar test was used to compare diagnoses based on a proportion of >40% CVS+ WML with diagnoses made using DIS/DIT criteria applied at a single time point on the same MRI datasets. Results: In 17 pwRMS, 239 WML were identified. Inter-observer agreement for the presence of the CVS was good (κ = 0.63). 88% of WML were CVS+. All pwRMS met the diagnostic criterion (CVS+ in >40% of WML). All pwRMS met current MRI DIS criteria, but only 1/17 met DIT criteria using MRI acquired at a single time point. Conclusions: FLAIR* reliably enables detection of a characteristic histological feature of MS WML, the central vein, in vivo. This may simplify the diagnosis of MS. Prospective studies in people with clinically isolated syndrome suggestive of demyelination are needed to confirm the diagnostic value of CVS detected using FLAIR*. P502 A longitudinal study of spinal cord atrophy in progressive multiple sclerosis Background: Spinal cord atrophy is strongly associated with physical disability in multiple sclerosis (MS) and has previously been used as a secondary outcome measure in clinical trials in progressive MS. However, the routine implementation of this measure has been limited by technical constraints, particularly poor reproducibility and insensitivity to small changes. We have recently reported a reproducible method for measuring upper cervical cord cross-sectional area (UCCA) in MS that combines 3D phase sensitive inversion recovery (PSIR) imaging and an active surface model (ASM). Objectives: To measure spinal cord atrophy by using this new methodology in a progressive MS cohort at one-year follow-up, and assessing its association with physical disability. Methods: We recruited 31 progressive patients: 18 with secondary progressive (SP), 13 primary progressive (PP) MS and ten controls. Physical disability was estimated at baseline and oneyear follow-up using the expanded disability status scale (EDSS). All subjects had 3T magnetic resonance imaging (MRI) of their cervical cord at both time points. The MRI protocol included a 3D-PSIR acquisition centred at C2/C3 with resolution of 0.5 x 0.5 x 3 mm 3 and UCCA was measured from these images using the ASM. To measure differences between MS and controls and changes from baseline to follow-up, unpaired and paired t-tests were used; univariate correlations between UCCA and EDSS were calculated using Spearman's rank correlation coefficient. Results: At baseline, progressive MS subjects (PP and SPMS combined) had a smaller UCCA than controls (68.13mm 2 ± 10,89 vs. 83.21mm 2 ± 7,92, p = 0.0002). There was a significant progression of clinical disability in MS patients (p= 0.0001) and a significant decrease in UCCA in both patient groups over one year (decrease in PPMS: 1.44mm 2 , 2.02%, SPMS: 1.33mm 2 , 2.03%). A reduction of UCCA in healthy controls was not detected. Thirteen of the 31 patients had an increase in their EDSS during the 12-month period, and they exhibited a greater reduction in cord area during the year (decrease in UCCA: 2.08 mm 2 ± 4,16 vs 0.87 mm 2 ± 0,35; p = 0.023) compared with the 18 patients whose disability status was unchanged. Conclusions: This newly developed method detects change in UCCA over the relatively short period of one year in both SP and PPMS patients. These results support the use of this imaging biomarker as a potential primary endpoint in future trials of neuroprotection in progressive MS. P503 Development of gray matter atrophy is associated with disability progression in patients with CIS: a 4 year follow up study Background: Although multiple sclerosis (MS) was originally considered to be a disease affecting predominantly the white matter (WM), pathological changes of gray matter (GM) are increasingly recognized as an important determinant of neurological sustained disability progression (SDP) and increased relapse activity in MS patients. Objectives: To investigate the association between the development of GM atrophy and clinical disease progression in patients with clinicaly isolated syndrome (CIS). Methods: This prospective, observational, 4-year follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks SDP and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were Multiple Sclerosis Journal 2014; 20: (S1) 285-496 investigated by mixed-effect model analysis after correction for multiple comparisons. Results: SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), decreased whole brain (p = .025), GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed increased rate of progression of number of new/ enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes. Conclusions: This study showed that cortical GM atrophy is associated with development of the SDP in and conversion to CDMS in patients with CIS patients on a standard disease-modifying therapy (DMT). To the best of our knowledge, this is the first follow-up study reported to date on the evolution of GM pathology and development of SDP in a homogenous sample of CIS patients treated with DMT. Further research is needed to clarify the nature and extent of GM pathology in CIS and to investigate the effect of newly introduced DMTs on prevention of GM pathology. P504 Microstructural white matter damage in fatigued multiple sclerosis patients: a DTI-TBSS study A Background: Fatigue is one of the most common and disabling symptoms in Multiple Sclerosis (MS). Yet the relationship between fatigue and normal appearing white matter (NAWM) damage is still unclear. Objectives: to investigate the microstructural damage of the NAWM and its relationship to fatigue in relapsing-remitting MS (RRMS). Methods: Sixty-three RRMS were enrolled in the study and, after the evaluation by the Fatigue Severity Scale (FSS), classified as fatigued (F-RRMS; FSS score > 45; N=33) and non-fatigued (NF-RRMS; FSS score < 36; N=30). Thirty-one age-and sexmatched, non-fatigued, healthy controls (HC) were used as control group. A clinical evaluation, including the EDSS score, was obtained in all RRMS patients . Al subjects underwent a 3T MRI including conventional and DTI sequences. Gray (GM) and white matter (WM) atrophy were estimated using SIENAX software. WM focal lesions were identified and lesion volume (LV) and Lesion Probability Maps (LPM) were computed. The microscopic NAWM damage was explored by Tract Based Spatial Statistic (TBSS) analysis, using LPM to exclude voxels were WM lesion frequency was higher than 5%. Results: F-RRMS and NF-RRMS did not show any significant difference in age, gender, disease duration, EDSS, LV and GM/ WM atrophy measures. TBSS-derived metrics (mean diffusivity [MD], fractional anisotropy [FA] and radial diffusivity [RD]) of the reconstructed NAWM skeleton were significantly and diffusely altered when comparing RRMS with HC. A widespread FA reduction and MD increase was found in the NAWM of F-RRMS when compared to NF-RRMS (uncorrected threshold, p<0.001). These findings mostly located at the level of thalamus as well as motor and premotor cortices, predominantly in the right hemisphere. In the correlation analysis a significant relationship was found between DTI-derived measures (MD and RD) of the NAWM skeleton, particularly at the level of fronto-parieto-insular regions, and FSS scores. Conclusions: a widespread microstructural NAWM damage, especially located in the right motor/pre-motor cortex and thalamus, might be a critical factor in determining fatigue in RRMS patients. The relevance and specificity of such finding is further emphasized by the lack of significant differences in GM/WM atrophy and LV between F-RRMS and NF-RRMS. Background: For many years, multiple sclerosis (MS) has been considered as a "white matter (WM)" disease. However, recent studies show that MS is a "whole-brain" disease. Although conventional MRI techniques have good capability of detecting WM lesions, they can barely detect "invisible" damages in normal appearing white matter (NAWM) and cortical gray matter (GM). Previously we demonstrated that MRI-based Gradient Echo Plural Contrast Imaging (GEPCI) technique, allowing simultaneous generation of naturally co-registered multi-contrast images (T1-weighted, T2 * or R2 * maps and frequency maps) from a single MR scan, can provide important information on tissue damage in MS lesions. Objectives: In this paper we use GEPCI technique to quantitatively assess those "invisible" tissue damages in NAWM and GM of MS subjects with different subtypes. Methods: All studies were approved by local IRB. High resolution (1x1x3mm 3 ) brain GEPCI data (T1 weighted and R2* maps) were acquired from 10 relapsing remitting (RM), 10 primary progressive (PP) and 10 secondary progressive (SP) MS subjects using a multi-gradient-echo sequence with 10 echoes on a 3T SIEMENS Magnetom Trio. By using a previously developed theoretical model, R2 * was separated into two components: cellular part (R2 * c ) and vascular part (R2'). Standard clinical MPRAGE images were also collected and put into "FreeSurfer" to generate brain segmentation. By using "FLIRT" tool in "FSL", MPRAGE images were registered to GEPCI-T1-weighted images, which are naturally co-registered with GEPCI R2 * /R2 * c /R2' maps. Median values of R2 * /R2 * c /R2' were calculated for all FreeSurfer regions in each subject. A previously acquired healthy baseline data was used to calculate z-scores of MS subjects in all FreeSurfer regions. Poster session 2, 20 (s1) Multiple Sclerosis Journal 2014; 20: (S1) 285-496 Tissue in regions that have low z-scores (< -1.96) was considered damaged. Results: We found that 30% of RR, 50% of PP and 50% of SP subjects have damage in NAWM. For cortical GM, the percentages are 20%, 40% and 70% correspondingly. For the globuspallidus region R2* values are higher than normal: 50% of RR, 20% of PP and 10% of SP have z-score > 1.96. Conclusions: The results in this study shows that quantitative GEPCI R2 * /R2 * c measurements can be considered as robust biomarkers to evaluate "invisible" tissue damages in NAWM and cortical GM, which can be difficult to evaluate using conventional methods. This new analysis clearly shows possible damages in the whole brain for subjects with different MS subtypes, thus has a great potential in clinical use. P506 Functional neuroimaging of inattentional blindness in multiple sclerosis Background: Inattentional blindness (IB) refers to the failure to notice a salient stimulus in one's field of vision while conducting an attention-demanding task. Although patients with MS often show cognitive deficits, evidence suggests that they are paradoxically less likely to exhibit IB compared to healthy controls. However, the neural correlates underlying IB in MS patients are not known. Objectives: To explore the neural correlates of IB in MS patients using functional magnetic resonance imaging (fMRI). Methods: 26 patients with confirmed MS completed an IB task while undergoing fMRI. On each trial, subjects were asked to maintain fixation while identifying visual targets in their periphery. On critical trials, an unexpected stimulus simultaneously appeared with the targets. Trials were presented under conditions of IB, i.e. without priming for the unexpected stimulus and under conditions during which subjects were primed that the unexpected stimulus might appear and that they should watch for it. A questionnaire was also given post-test to determine each subject's awareness of the unexpected stimulus. This design allowed for 2 contrasts: Paradigm 1) A within-subjects comparison of activity on critical trials between the non-primed and primed conditions (n=9), and Paradigm 2) A comparison between subjects who always noticed the unexpected stimulus irrespective of priming (non-IB; n =13) versus those who did not see the unexpected stimulus in the non-primed trial only (IB; n =9). All other subjects were excluded from the analysis. Results: Across all subjects increased activity in bilateral frontal eye fields (FEF) was found during critical trials in Paradigm 1 (FWE-corrected, p < .005), consistent with the role of the FEF in goal-directed attention. Comparing neural activity in Paradigm 2 between IB and non-IB subjects, increased activity in the anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) was found in the IB patients (FWE-corrected, p < .005). Conclusions: Within MS patients, IB evokes activity in similar neural regions to that of healthy controls: namely, increased activity in ACC/mPFC, which have been implicated in non-conscious processing of stimuli. Future work is required to determine the mechanism underlying MS patients' decreased susceptibility to IB, likely reflective of their reduced attention resources. P507 The nature of white matter tract injury in relapsingremitting multiple sclerosis: a diffusion-tensor imaging study in relation to disease duration A Background: Diffusion-tensor imaging (DTI) studies in multiple sclerosis (MS) reveal white matter (WM) injury with disease progression. Our approach utilizes whole-brain and voxelwise approaches to extensively investigate alterations in white matter and observe their progression over space and time. Objectives: To evaluate microstructural white matter damage in relapsing-remitting multiple sclerosis (RRMS) as measured by brain DTI in patients with varying periods of disease duration. Methods: Axial DTI data was acquired along 31 directions at 2.6mm slices with single shot echo-planar imaging and 2 images without diffusion weighting (b=0) for 90 RRMS patients (age 37.6±1.0 years, 66 females) and 25 healthy controls (age: 35.1±2.2 years; 14 females) on a 3.0T scanner. Patients were grouped to short (< 1 year), moderate (1-6 years) and long (6-10 years) disease duration periods. Whole-brain and voxelwise analyses of fractional anisotropy (FA) data were carried out using tract-based spatial statistics (TBSS). Threshold-free cluster enhancement (TFCE) was performed for voxelwise analysis alongside the JHU ICBM-DTI-81 atlas for major WM tract identification. Student two-tailed unpaired t-test was performed on FA in each significant region´s clusters for between-group analyses. Results: Whole-brain WM FA measurements showed a significant decrease between healthy controls and the short disease duration group (0.47±0.02 versus 0.44±0.02, p < 0.001), as well as between medium and long disease duration groups (0.44±0.02 versus 0.43±0.02, p < 0.01), but failed to show significance between short and medium disease duration groups (0.44±0.02 versus 0.44±0.02, p =0.95). On further inspection, voxelwise analysis revealed diffuse FA reduction spanning a skeletal area of 60,784 of 195,350 total voxels and affecting 38 major WM tracts when comparing healthy controls and the short duration group. FA reduction was also shown in 30 major WM tracts when comparing the long and medium duration groups, affecting 42,212 of 192,208 skeletal voxels. Conclusions: DTI data revealed significant disruptive injuries related to disease progression in RRMS patients. Initially, an acute episode of widespread alterations in WM tracts is seen in the first year after diagnosis; however, these changes slow to a plateau in patients with medium disease duration and later demonstrate significant, widespread WM changes in patients with long disease duration. Our findings signify a distinct, non-linear temporal pattern to changes in WM microstructure. Poster session 2, 20 (s1)
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="">doi:10.1177/1352458514547846</a> <a target="_blank" rel="external noopener" href="">pmid:25205049</a> <a target="_blank" rel="external noopener" href="">pmcid:PMC4244175</a> <a target="_blank" rel="external noopener" href="">fatcat:gj757y4jlvejpnrfw22guoit7m</a> </span>
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