Abstract

Background/Purpose: Inflammation in the meninges is increasingly recognized as a critical component of the underlying pathophysiology of multiple sclerosis (MS). Histopathologic data suggests direct links between meningeal inflammation and both local and distant cortical demyelination and axonal loss. Neuroimaging studies of leptomeningeal enhancement (LME), a possible surrogate of meningeal inflammation, show a relationship between LME and cortical atrophy, although findings relating LME to cortical lesions (CLs) have been more inconsistent. In this study, we aimed to evaluate the interrelationship between LME, CLs, and more distant neuronal atrophy through evaluation of retinal thickness by optical coherence tomography (OCT).

Methods: Forty participants with MS underwent whole brain 7T imaging on a Philips Achieva scanner with a volume transmit/32 channel receive head coil and optical coherence tomography on a Heidelberg Engineering Spectralis spectral domain OCT scanner at baseline, along with annual follow up OCT images. 7T scans involved pre- and post-contrast acquisition of magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) sequences acquired at 0.7 mm x 0.688 mm x 0.68 mm resolution and a magnetization prepared fluid attenuated inversion recovery (MPFLAIR) image at 0.7mm³ isotropic resolution. MRI images were reviewed for LME and CLs and processed for segmented volumes. OCT images underwent segmentation for individual retinal layers. MRI and OCT data were evaluated using correlation testing and mixed models regression, adjusted for age, sex, treatment status, and optic neuritis history.

Results: The cohort consisted of 26 (65%) females and were mostly of the relapsing-remitting phenotype (30/40 (75%). Thirty-two (80%) subjects had at least one focus of LME and all had CLs on 7T MRI. Baseline ganglion cell/inner plexiform (GCIP) layer and average macular thickness (AMT) correlated with normalized CL volume (r = -0.45, p = 0.006 and r = -0.34, p = 0.049 respectively). Macular RNFL (mRNFL) and GCIP thickness and AMT were -4.60 (-7.85, -1.35) μm, -8.12 (-14.16, -2.08) μm, and 15.073 (-28.61, -1.54) μm thinner, respectively, if LME was present (p = 0.006, 0.009, and 0.030, respectively). In subjects in whom spread/fill-sulcal pattern LME was present at baseline, mRNFL thickness declined -0.84 (-1.61, -0.07) μm/year faster (p = 0.033) and OPL thickness declined -1.23 (-2.33, -0.13) μm/year faster (p = 0.029).

Conclusion: This study provides support for a relationship between MRI findings of cortical pathology and LME and thinning of retinal layers as measured by OCT. These associations suggest meningeal inflammation may be a common link resulting in widespread demyelination, neuronal loss, and axonal degeneration throughout the CNS and the retina.

Abstract

Background/Purpose: Inflammation in the meninges is increasingly recognized as a critical component of the underlying pathophysiology of multiple sclerosis (MS). Histopathologic data suggests direct links between meningeal inflammation and both local and distant cortical demyelination and axonal loss. Neuroimaging studies of leptomeningeal enhancement (LME), a possible surrogate of meningeal inflammation, show a relationship between LME and cortical atrophy, although findings relating LME to cortical lesions (CLs) have been more inconsistent. In this study, we aimed to evaluate the interrelationship between LME, CLs, and more distant neuronal atrophy through evaluation of retinal thickness by optical coherence tomography (OCT).

Methods: Forty participants with MS underwent whole brain 7T imaging on a Philips Achieva scanner with a volume transmit/32 channel receive head coil and optical coherence tomography on a Heidelberg Engineering Spectralis spectral domain OCT scanner at baseline, along with annual follow up OCT images. 7T scans involved pre- and post-contrast acquisition of magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) sequences acquired at 0.7 mm x 0.688 mm x 0.68 mm resolution and a magnetization prepared fluid attenuated inversion recovery (MPFLAIR) image at 0.7mm³ isotropic resolution. MRI images were reviewed for LME and CLs and processed for segmented volumes. OCT images underwent segmentation for individual retinal layers. MRI and OCT data were evaluated using correlation testing and mixed models regression, adjusted for age, sex, treatment status, and optic neuritis history.

Results: The cohort consisted of 26 (65%) females and were mostly of the relapsing-remitting phenotype (30/40 (75%). Thirty-two (80%) subjects had at least one focus of LME and all had CLs on 7T MRI. Baseline ganglion cell/inner plexiform (GCIP) layer and average macular thickness (AMT) correlated with normalized CL volume (r = -0.45, p = 0.006 and r = -0.34, p = 0.049 respectively). Macular RNFL (mRNFL) and GCIP thickness and AMT were -4.60 (-7.85, -1.35) μm, -8.12 (-14.16, -2.08) μm, and 15.073 (-28.61, -1.54) μm thinner, respectively, if LME was present (p = 0.006, 0.009, and 0.030, respectively). In subjects in whom spread/fill-sulcal pattern LME was present at baseline, mRNFL thickness declined -0.84 (-1.61, -0.07) μm/year faster (p = 0.033) and OPL thickness declined -1.23 (-2.33, -0.13) μm/year faster (p = 0.029).

Conclusion: This study provides support for a relationship between MRI findings of cortical pathology and LME and thinning of retinal layers as measured by OCT. These associations suggest meningeal inflammation may be a common link resulting in widespread demyelination, neuronal loss, and axonal degeneration throughout the CNS and the retina.

Abstract

Background/Purpose: Inflammation in the meninges is increasingly recognized as a critical component of the underlying pathophysiology of multiple sclerosis (MS). Histopathologic data suggests direct links between meningeal inflammation and both local and distant cortical demyelination and axonal loss. Neuroimaging studies of leptomeningeal enhancement (LME), a possible surrogate of meningeal inflammation, show a relationship between LME and cortical atrophy, although findings relating LME to cortical lesions (CLs) have been more inconsistent. In this study, we aimed to evaluate the interrelationship between LME, CLs, and more distant neuronal atrophy through evaluation of retinal thickness by optical coherence tomography (OCT).

Methods: Forty participants with MS underwent whole brain 7T imaging on a Philips Achieva scanner with a volume transmit/32 channel receive head coil and optical coherence tomography on a Heidelberg Engineering Spectralis spectral domain OCT scanner at baseline, along with annual follow up OCT images. 7T scans involved pre- and post-contrast acquisition of magnetization prepared 2 rapid acquisition gradient echo (MP2RAGE) sequences acquired at 0.7 mm x 0.688 mm x 0.68 mm resolution and a magnetization prepared fluid attenuated inversion recovery (MPFLAIR) image at 0.7mm³ isotropic resolution. MRI images were reviewed for LME and CLs and processed for segmented volumes. OCT images underwent segmentation for individual retinal layers. MRI and OCT data were evaluated using correlation testing and mixed models regression, adjusted for age, sex, treatment status, and optic neuritis history.

Results: The cohort consisted of 26 (65%) females and were mostly of the relapsing-remitting phenotype (30/40 (75%). Thirty-two (80%) subjects had at least one focus of LME and all had CLs on 7T MRI. Baseline ganglion cell/inner plexiform (GCIP) layer and average macular thickness (AMT) correlated with normalized CL volume (r = -0.45, p = 0.006 and r = -0.34, p = 0.049 respectively). Macular RNFL (mRNFL) and GCIP thickness and AMT were -4.60 (-7.85, -1.35) μm, -8.12 (-14.16, -2.08) μm, and 15.073 (-28.61, -1.54) μm thinner, respectively, if LME was present (p = 0.006, 0.009, and 0.030, respectively). In subjects in whom spread/fill-sulcal pattern LME was present at baseline, mRNFL thickness declined -0.84 (-1.61, -0.07) μm/year faster (p = 0.033) and OPL thickness declined -1.23 (-2.33, -0.13) μm/year faster (p = 0.029).

Conclusion: This study provides support for a relationship between MRI findings of cortical pathology and LME and thinning of retinal layers as measured by OCT. These associations suggest meningeal inflammation may be a common link resulting in widespread demyelination, neuronal loss, and axonal degeneration throughout the CNS and the retina.

Background

Alterations in the myelination and iron distribution of the cerebral cortex underlie abnormal cortical function in multiple sclerosis (MS). Due to the pathology, the transition from the inner layers to the outer layers (from white matter to the pial surface) of the cortex reflects changes in the cyto- and myeloarchitecture of the cortex. Cortical demyelination and iron deposition are relevant aspects of tissue damage and microstructural changes may affect each layer in the cortex differently.

Objectives

The purpose of this study was to assess the distribution of quantitative MRI (qMRI) measurements on the whole cortex and its sensitivity as clinically accessible biomarkers of grey matter (GM) pathology in MS.

Methods

45 participants with MS underwent 7T MRI of the brain. Magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) was processed for T₁-weighted (T₁w) images and a T₁-map. Multi-echo gradient echo images were processed for quantitative susceptibility (χ) and R₂* mapping. Cortical GM volumes were segmented into nine cortical layers and relaxometry metrics were calculated within layers. The layers were grouped in three regions, inner (0-30%), middle (31-70%) and outer region (71-100%), and the distributions of these relaxometry metrics throughout the cortical thickness were compared to collect disability scales.

Results

Significant Spearman correlations were found with Expanded Disability Status Scale (EDSS) for the slope of the linear regression of the median values in the inner region (T₁: r = -0.587, p < 0.001; R₂*: r = 0.610, p < 0.001; χ: r = 0.416, p < 0.010). With timed 25-foot walk (T25FW) (T₁: r = -0.429, p < 0.010; R₂*: r = 0.558, p < 0.001). With symbol digit modalities test (SDMT), middle region (T₁: r = -0.389, p < 0.010; R₂*: r = -0.328, p < 0.050; χ: r = -0.301, p < 0.050). With EDSS, outer region (R₂*: r = -0.312, p < 0.050).

Conclusions

Cortical layer 7T qMRI analyses revealed pattern-specific distributions and regional relationships with disability in MS. These associations might show the increase in homogeneous myelin distribution and heterogeneous iron distribution locally throughout the cortical thickness. The strong relationships found between disability scales warrant further exploration as a novel outcome measure.

Background

Recent advancements in quantitative neuroimaging have revealed signal heterogeneity in multiple sclerosis (MS) brains. Although most work focuses on central tendency measures (i.e., mean or median), distribution features (i.e., density profile, skewness, kurtosis) of quantitative metrics from magnetic resonance image (MRI) may also provide insightful information about disease severity and progression.

Objectives

We aimed to characterize white matter lesion (WML), normal-appearing white matter (NAWM), and cortical gray matter (GM) in MS brains utilizing distribution features of T₁ values from 7-Tesla (7T) MRI to demonstrate their potential as biomarkers of MS disease phenotype and disability.

Methods

Forty-eight participants with MS underwent brain MRI on a 7T scanner. Magnetization prepared 2 rapid gradient echo (MP2RAGE) image was acquired, and quantitative T₁ relaxation times were calculated from two inversion images from the acquisition. T₁-weighted image reconstructed from MP2RAGE was used for the segmentation of the brain into WML, NAWM, and GM tissue types. T₁ values of all participants were concatenated and subgrouped by either disability or disease subtype. T₁ distributions in three tissue segments were compared using cumulative distribution function and Two-sample Kolmogorov-Smirnov test (D-statistic). Associations of various T₁ features with clinical measures were assessed by Spearman or Pearson methods with controlling for age, as appropriate.

Results

Concatenated T₁ distribution of participants’ WML in groups with a higher disability or more progressive MS phenotype appeared wider and shifted toward a higher T₁ value. For example, the higher disability group had a higher IQR of T₁ (p = 0.040) and a higher median T₁ (p = 0.018). The distribution profile of WML was distinctively different between low and high EDSS groups and relapsing versus progressive MS (D = 0.323, p = < 0.001; D = 0.314, p = < 0.001 respectively). Distribution profiles of NAWM and GM were also significantly different between groups, but the magnitude of the difference was smaller (D = 0.058 and D = 0.024, respectively). Despite the difference in the appearance of distribution profiles in WML between groups, skewness and kurtosis were not significantly different. Disability (measured as Expanded Disability Status Scale: EDSS) was significantly correlated with median T₁ (rho = 0.405, p = 0.005) and skewness of T₁ (rho = -0.301, p = 0.040) in WML, and median T₁ (rho = 0.435, p = 0.002) and IQR of T₁ (rho = 0.452, p = 0.001) in NAWM. Neither central tendency nor distribution measures in GM significantly correlated with EDSS.

Conclusions

Our study suggests that differences in T₁ distribution between groups reflect increasing T₁ values of WML as disease advances toward more severe status (i.e., higher disability or progressive MS). This finding supports T₁ measures as a potential in vivo biomarker in the diagnosis and prognosis of MS brains.

Background

Recent imaging data in multiple sclerosis (MS) suggests that chronic-active lesions and inactive lesions can be differentiated based on the presence of paramagnetic rims on gradient-echo (GRE). At autopsy, chronic-active lesions show significant demyelination, oligodendrocyte loss, and outer rims of iron laden macrophages and activated microglia. Confirmation of the destructive nature of these lesions on MRI would provide in vivo evidence of their consequences. Further, evidence of local blood-brain barrier (BBB) breakdown in these lesions would provide further validation of their chronic-active state, along with suggesting a possible opportunity for therapeutic intervention.

Objectives

We aimed to determine if white matter lesions (WMLs) with paramagnetic rims show greater alterations in multiple signal characteristics, including our novel metric for BBB breakdown, Magnetization prepared 2 rapid gradient echo (MP2RAGE) ΔT1 mapping.

Methods

MP2RAGE and GRE images of the brain were acquired on 36 participants with MS on a 7T MRI before and after contrast. GRE images were processed for R2* and quantitative susceptibility maps (QSM). MP2RAGE was processed for T1 mapping and all images were registered to the pre-contrast T1-weighted (T1-w) image. ΔT1 maps were created by subtracting pre and post-contrast T1 maps. All WMLs were masked on T1-w and masks were separately created for lesions with visible paramagnetic rims on QSM. T1, ΔT1, χ (from QSM), and R2* values were compared across lesion types using a linear mixed effects model and Wilcoxon rank sum testing.

Results

Mean pre-contrast T1 was significantly higher in rimmed lesions (2.323, SE = 0.03964) compared to non-rimmed lesions (2.113, SE = 0.05791; p<0.001). Mean and median ΔT1 values were not significantly different in non-rimmed lesions versus rimmed lesions. Median pre-contrast χ values were significantly smaller in rimmed lesions (-0.00581, SE = 0.00277) versus non-rimmed lesions (-0.01298, SE = 0.003332; p = 0.011). Pre-contrast median R2* was significantly lower in rimmed lesions (24.55, SE = 0.8378) versus non-rimmed lesions (28.04, SE = 0.8919; p<0.001).

Conclusions

Elevated T1 and reduced χ and R2* in rimmed lesions in this study are confirmatory of greater demyelination and tissue destruction in this lesion subtype. The lack of significant difference in ΔT1 values suggests that there is no evidence of additional BBB breakdown in chronic-active lesions as measured on MRI.

Abstract

Magnetic resonance imaging (MRI) is the main diagnostic and prognostic tool used in the study and treatment of patients with multiple sclerosis (MS). Visualization of MS pathology by MRI has brought about substantial advances in MS care, including earlier and more accurate diagnoses and the ability to monitor the effects of treatment and visualize subclinical disease activity. Despite these advances, it is well known that standard, clinical MRI fails to visualize much of MS-related pathology. Although current MRI performs well as a tool to measure white matter (WM) inflammation in MS, its ability to quantify gray matter (GM) pathology, meningeal inflammation, neurodegeneration, chronic inflammatory changes, and myelin tissue content is limited. For this reason, researchers continue to strive towards development of new imaging technologies –hoping to bring us closer to in vivo quantification of MS changes analogous to post-mortem histopathology. One such technology is ultra-high field, 7 Tesla (7T) MRI. 7T MRI has been applied to MS and has demonstrated superiority in visualization of WM lesions and GM lesions. Further, 7T MRI has led to the identification of novel biomarkers, such as the central vein sign (CVS), WM lesions with paramagnetic rims, and leptomeningeal inflammation (LME), among others.

In this talk, we will review the data available on application of these techniques in vivo, and review clinical correlations and clinical outcome prediction. Further, with the approval of 7T MRI as a medical device by the FDA in recent years, we will review the potential applications of 7T scanners in clinical settings and for clinical trials.

Abstract

Magnetic resonance imaging (MRI) is the main diagnostic and prognostic tool used in the study and treatment of patients with multiple sclerosis (MS). Visualization of MS pathology by MRI has brought about substantial advances in MS care, including earlier and more accurate diagnoses and the ability to monitor the effects of treatment and visualize subclinical disease activity. Despite these advances, it is well known that standard, clinical MRI fails to visualize much of MS-related pathology. Although current MRI performs well as a tool to measure white matter (WM) inflammation in MS, its ability to quantify gray matter (GM) pathology, meningeal inflammation, neurodegeneration, chronic inflammatory changes, and myelin tissue content is limited. For this reason, researchers continue to strive towards development of new imaging technologies –hoping to bring us closer to in vivo quantification of MS changes analogous to post-mortem histopathology. One such technology is ultra-high field, 7 Tesla (7T) MRI. 7T MRI has been applied to MS and has demonstrated superiority in visualization of WM lesions and GM lesions. Further, 7T MRI has led to the identification of novel biomarkers, such as the central vein sign (CVS), WM lesions with paramagnetic rims, and leptomeningeal inflammation (LME), among others.

In this talk, we will review the data available on application of these techniques in vivo, and review clinical correlations and clinical outcome prediction. Further, with the approval of 7T MRI as a medical device by the FDA in recent years, we will review the potential applications of 7T scanners in clinical settings and for clinical trials.

Abstract

Magnetic resonance imaging (MRI) is the main diagnostic and prognostic tool used in the study and treatment of patients with multiple sclerosis (MS). Visualization of MS pathology by MRI has brought about substantial advances in MS care, including earlier and more accurate diagnoses and the ability to monitor the effects of treatment and visualize subclinical disease activity. Despite these advances, it is well known that standard, clinical MRI fails to visualize much of MS-related pathology. Although current MRI performs well as a tool to measure white matter (WM) inflammation in MS, its ability to quantify gray matter (GM) pathology, meningeal inflammation, neurodegeneration, chronic inflammatory changes, and myelin tissue content is limited. For this reason, researchers continue to strive towards development of new imaging technologies –hoping to bring us closer to in vivo quantification of MS changes analogous to post-mortem histopathology. One such technology is ultra-high field, 7 Tesla (7T) MRI. 7T MRI has been applied to MS and has demonstrated superiority in visualization of WM lesions and GM lesions. Further, 7T MRI has led to the identification of novel biomarkers, such as the central vein sign (CVS), WM lesions with paramagnetic rims, and leptomeningeal inflammation (LME), among others.

In this talk, we will review the data available on application of these techniques in vivo, and review clinical correlations and clinical outcome prediction. Further, with the approval of 7T MRI as a medical device by the FDA in recent years, we will review the potential applications of 7T scanners in clinical settings and for clinical trials.