Elizabeth Monohan

Measuring Longitudinal Myelin Water Fraction in New Multiple Sclerosis Lesions

Objectives Investigating the potential of myelin repair strategies in multiple sclerosis (MS) requires an understanding of myelin dynamics during lesion evolution. The objective of this study is to longitudinally measure myelin water fraction (MWF), an MRI biomarker of myelin, in new MS lesions and to identify factors that influence their subsequent myelin content. Methods Twenty-three MS patients were scanned with whole-brain Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) MWF mapping at baseline and median follow-up of 6 months. Eleven healthy controls (HC) confirmed the reproducibility of FAST-T2 in white matter regions of interests (ROIs) similar to a lesion size. A random-effect-model was implemented to determine the association between baseline clinical and lesion variables and the subsequent MWF. Results ROI-based measurements in HCs were highly correlated between scans [mean r = 0.893 (.764–.967)]. In MS patients, 38 gadolinium enhancing (Gd+) and 25 new non-enhancing (Gd−) T2 hyperintense lesions (5.7 months, ±3.8) were identified. Significant improvement in MWF was seen in Gd+ lesions (0.035 ± 0.029, p < 0.001) as compared to Gd− lesions (0.006 ± 0.017, p = 0.065). In the model, a higher baseline MWF (p < 0.001) and the presence of Gd (p < 0.001) were associated with higher subsequent MWF. Conclusions FAST T2 provides a clinically feasible method to quantify MWF in new MS lesions. The observed influence of baseline MWF, which represents a combined effect of both resolving edema and myelin change within acute lesions, suggests that the extent of initial inflammation impacts final myelin recovery.

Feasibility and reproducibility of whole brain myelin water mapping in 4 minutes using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) at 3T.

To develop and measure the reproducibility of 4‐min whole brain myelin water fraction (MWF) mapping using fast acquisition with spiral trajectory and T2prep (FAST‐T2) sequence at 3T.

Modeling the Relationship among Gray Matter Atrophy, Abnormalities in Connecting White Matter, and Cognitive Performance in Early Multiple Sclerosis

BACKGROUND AND PURPOSE: Quantitative assessment of clinical and pathologic consequences of white matter abnormalities in multiple sclerosis is critical in understanding the pathways of disease. This study aimed to test whether gray matter atrophy was related to abnormalities in connecting white matter and to identify patterns of imaging biomarker abnormalities that were related to patient processing speed. MATERIALS AND METHODS: Image data and Symbol Digit Modalities Test scores were collected from a cohort of patients with early multiple sclerosis. The Network Modification Tool was used to estimate connectivity irregularities by projecting white matter abnormalities onto connecting gray matter regions. Partial least-squares regression quantified the relationship between imaging biomarkers and processing speed as measured by the Symbol Digit Modalities Test. RESULTS: Atrophy in deep gray matter structures of the thalami and putamen had moderate and significant correlations with abnormalities in connecting white matter (r = 0.39–0.41, P < .05 corrected). The 2 models of processing speed, 1 for each of the WM imaging biomarkers, had goodness-of-fit (R2) values of 0.42 and 0.30. A measure of the impact of white matter lesions on the connectivity of occipital and parietal areas had significant nonzero regression coefficients. CONCLUSIONS: We concluded that deep gray matter regions may be susceptible to inflammation and/or demyelination in white matter, possibly having a higher sensitivity to remote degeneration, and that lesions affecting visual processing pathways were related to processing speed. The Network Modification Tool may be used to quantify the impact of early white matter abnormalities on both connecting gray matter structures and processing speed.

MRI Analysis of White Matter Myelin Water Content in Multiple Sclerosis: A Novel Approach Applied to Finding Correlates of Cortical Thinning

A novel lesion-mask free method based on a gamma mixture model was applied to myelin water fraction (MWF) maps to estimate the association between cortical thickness and myelin content, and how it differs between relapsing-remitting (RRMS) and secondary-progressive multiple sclerosis (SPMS) groups (135 and 23 patients, respectively). It was compared to an approach based on lesion masks. The gamma mixture distribution of whole brain, white matter (WM) MWF was characterized with three variables: the mode (most frequent value) m1 of the gamma component shown to relate to lesion, the mode m2 of the component shown to be associated with normal appearing (NA) WM, and the mixing ratio (λ) between the two distributions. The lesion-mask approach relied on the mean MWF within lesion and within NAWM. A multivariate regression analysis was carried out to find the best predictors of cortical thickness for each group and for each approach. The gamma-mixture method was shown to outperform the lesion-mask approach in terms of adjusted R2, both for the RRMS and SPMS groups. The predictors of the final gamma-mixture models were found to be m1 (β = 1.56, p < 0.005), λ (β = −0.30, p < 0.0005) and age (β = −0.0031, p < 0.005) for the RRMS group (adjusted R2 = 0.16), and m2 (β = 4.72, p < 0.0005) for the SPMS group (adjusted R2 = 0.45). Further, a DICE coefficient analysis demonstrated that the lesion mask had more overlap to an ROI associated with m1, than to an ROI associated with m2 (p < 0.00001), and vice versa for the NAWM mask (p < 0.00001). These results suggest that during the relapsing phase, focal WM damage is associated with cortical thinning, yet in SPMS patients, global WM deterioration has a much stronger influence on secondary degeneration. Through these findings, we demonstrate the potential contribution of myelin loss on neuronal degeneration at different disease stages and the usefulness of our statistical reduction technique which is not affected by the typical bias associated with approaches based on lesion masks.

Profilometry: A new statistical framework for the characterization of white matter pathways, with application to multiple sclerosis

Aims: describe a new “profilometry” framework for the multimetric analysis of white matter tracts, and demonstrate its application to multiple sclerosis (MS) with radial diffusivity (RD) and myelin water fraction (MWF). Methods: A cohort of 15 normal controls (NC) and 141 MS patients were imaged with T1, T2 FLAIR, T2 relaxometry and diffusion MRI (dMRI) sequences. T1 and T2 FLAIR allowed for the identification of patients having lesion(s) on the tracts studied, with a special focus on the forceps minor. T2 relaxometry provided MWF maps, while dMRI data yielded RD maps and the tractography required to compute MWF and RD tract profiles. The statistical framework combined a multivariate analysis of covariance (MANCOVA) and a linear discriminant analysis (LDA) both accounting for age and gender, with multiple comparison corrections. Results: In the single‐case case study the profilometry visualization showed a clear departure of MWF and RD from the NC normative data at the lesion location(s). Group comparison from MANCOVA demonstrated significant differences at lesion locations, and a significant age effect in several tracts. The follow‐up LDA analysis suggested MWF better discriminates groups than RD. Discussion and conclusion: While progress has been made in both tract‐profiling and metrics for white matter characterization, no single framework for a joint analysis of multimodality tract profiles accounting for age and gender is known to exist. The profilometry analysis and visualization appears to be a promising method to compare groups using a single score from MANCOVA while assessing the contribution of each metric with LDA. Hum Brain Mapp 37:989–1004, 2016.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation

OBJECTIVE The objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. METHODS Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patients white matter (VT ratio=VTr), to consider physiologic variability. RESULTS Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter. CONCLUSION A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

Differential Impact of Multiple Sclerosis on Cortical and Deep Gray Matter Structures in African Americans and Caucasian Americans.

African Americans with multiple sclerosis (AAwMS) have different disease phenotypes when compared to Caucasians Americans with MS (CAwMS). The pathologic basis of this difference in disease presentation is unknown.