Author Of 1 Presentation
HT05.03 - Presentation 03 - 7T MRI cerebral leptomeningeal enhancement predicts gray and white matter lesion accumulation one year later in relapsing-remitting multiple sclerosis
Abstract
Background
We recently showed that 7T MRI leptomeningeal enhancement (LME) is common in relapsing-remitting multiple sclerosis (RRMS) and is related to gray matter (cortical/thalamic) and white matter (WMLs) lesions.
Objectives
To investigate the dynamics of LME longitudinal change and relationship to subsequent lesion accumulation using 7T MRI.
Methods
25 RRMS subjects [age 44.5±11.2 years (mean±SD), 68% women, Expanded Disability Status Scale (EDSS) 2.0±1.5, 92% on disease-modifying therapy-DMT] and 12 healthy controls (HC) underwent brain 3D MP2RAGE and FLAIR 7T MRI with 0.7 mm3 voxels at baseline and ~1 year. Gadolinium-enhanced 3D-FLAIR was evaluated for LME. WMLs, cortical lesions (CLs) and thalamic lesions (TLs) were expert-quantified. Wilcoxon rank-sum, two-sample t-tests and Spearman’s correlations were investigated.
Results
LME was found in 17/25 (68%) RRMS subjects at baseline and 18/25 (72%) at follow-up vs. a single stable focus in 1/12 HC (8.3%). In the RRMS group, 42 LME foci [mean 2.5±1.1 (range 1-5) per LME+ subject] were identified at baseline versus 48 foci [2.7±1.2 (1-5)] at follow-up. LME foci number at follow-up was unchanged in 18 (72%) RRMS subjects, increased in 6 (24%), decreased in 1 (4%). All 6 subjects with increased LME foci were on treatment [glatiramer acetate, interferon-β (2), rituximab, ocrelizumab, fingolimod]. The subject with LME resolution was treated with ocrelizumab. LME+ subjects had an on-study increase in volume of WMLs (baseline 11.0±14.4 vs. follow-up 12.6±16.3 ml, p<0.001), CLs (0.85±1.2 vs. 1.0±1.4 ml, p=0.002) and TLs (0.103±0.093 vs. 0.117±0.099 ml, p=0.005), whereas LME- subjects had an increase only in WML volume (2.7±2.3 vs. 3.3±2.6 ml, p=0.023). Baseline LME foci number correlated with 1-year change in CL (r=0.36, p=0.078) and WML (r=0.50, p=0.010) volumes. Minimal EDSS change over 1 year was noted. We used these data as the basis for a sample size calculation for a hypothetical trial of a putative therapy that would reduce the rate of MRI lesion accrual by 80% over 1 year. For a single-arm study with 1-year run-in on standard therapy and 1 year on new treatment to achieve 80% power, sample sizes of n=46, n=56 and n=79 were calculated for CL volume, TL volume and LME foci number, respectively.
Conclusions
The evolution of cerebral LME may be a dynamic process in the short term in RRMS, providing a monitoring tool, with about one quarter of patients showing new foci at one year. LME may pose a risk for the subsequent development of new lesions in widespread brain regions, implicating meningeal involvement as a marker or mediator of increased disease severity.
Author Of 1 Presentation
LB1224 - Thalamic and whole brain atrophy are linked with white matter microglial activation: A [F-18]PBR06-PET study in multiple sclerosis (ID 2099)
Abstract
Background
Thalamic and whole brain atrophy have been extensively studied as biomarkers of neurodegeneration in multiple sclerosis but their mechanism is not clear. [F-18]PBR06-Positron Emission Tomography (PET) is a novel molecular imaging technique to assess microglial activation.
Objectives
To determine the relationship of thalamic and whole brain atrophy with white matter (WM) microglial activation in multiple sclerosis.
Methods
22 individuals (13 MS, including 8 relapsing-remitting and 5 secondary progressive, and 9 healthy control (HC)) subjects underwent 3T MRI and [F-18]PBR06-PET. Individualized z-score maps of WM microglial activation were generated by voxel-by-voxel comparison between each subject's PET SUVR images and a control dataset. Glial activity load on PET in WM (“GALP-WM”) was calculated as the sum of voxel-by-voxel z-scores ≥4 in the WM subjects and its logarithmic transformation (“ln-GALP”) was also obtained. "Z-max" score was calculated as the highest z-score in the WM matter averaged over surrounding 5 voxels. SIENAX and FSL-FIRST pipelines determined normalized brain parenchymal volume (BPV) and thalamic volumes (Th-V) respectively. A p-value <0.05 was considered statistically significant.
Results
Th-V and BPV were lower in MS vs. HC (19.7±2.2 vs. 22.4±1.6 ml, 1376.6±81.3 vs. 1475.1±70.9 ml, both p<0.01). GALP-WM, Z-max and ln-GALP were higher in MS vs. HC (18757.9±13646 vs. 7580.5±12216, 13.2±2.9 vs. 8.3±4.1, and 9.5±0.92 vs. 7.4±1.9, all p<0.05). Th-V and BPV were inversely correlated with WM microglial activation, represented by GALP-WM, Z-max and ln-GALP (r=-0.62, -0.66 and -0.62, all p<0.01 for Th-V and r=-0.68, -0.643 and -0.678, all p<0.01 for BPV) that remained significant after adjustment for age (all p<0.05).
Conclusions
Thalamic and whole brain atrophy are linked with white matter microglial activation in MS, representing a link between neuroinflammation and neurodegeneration across central nervous system compartments. Further investigation of the “GALP” method as a novel, individualized approach for evaluating glial activity in MS is warranted. Prospective longitudinal studies to determine the impact of therapeutically targeting microglial activation on neurodegeneration in MS patients are urgently needed.