Paramagnetic rim lesions are associated with higher white matter inflammation in MS
Poster No:
203
Submission Type:
Abstract Submission
Authors:
Ceren Tozlu1, Keith Jamison2, Yeona Kang3, Sandra Hurtado Rua4, Ulrike Kaunzner1, Thanh Nguyen2, Amy Kuceyeski5, Susan Gauthier2
Institutions:
1Weill Cornell Medicine, NYC, NY, 2Weill Cornell Medicine, New York, NY, 3Howard University, Washington, DC, 4Department of Mathematics and Statistics, Cleveland State University, Cleveland, OH, 5Cornell, Ithaca, NY
First Author:
Co-Author(s):
Sandra Hurtado Rua
Department of Mathematics and Statistics, Cleveland State University
Cleveland, OH
Department of Mathematics and Statistics, Cleveland State University
Cleveland, OH
Introduction:
Understanding the factors driving disease progression in multiple sclerosis (MS) is essential for achieving accurate prognosis and developing new therapeutic targets. Compartmentalized inflammation within the central nervous system (CNS) of patients with MS is believed to play a significant role in disease processes. Persistent smoldering inflammation in paramagnetic rim lesions (PRLs) - a subset of chronic lesions defined by a dense rim of iron-laden, pro-inflammatory immune cells - has been linked to more aggressive cognitive and ambulatory impairment [1-6]. However, it remains uncertain whether this correlation is due to the presence of PRLs themselves or other underlying, unmeasured factors such as inflammatory activity. The goal of our study was to explore whether inflammatory activity is increased along white matter (WM) tracts disrupted by PRLs and if the PRLs-related inflammation along the disrupted WM tracts is associated with disability in people with MS.
Methods:
Forty-four MS patients (aged 45.45 ± 13.82, 61.4% female) and 16 healthy controls (aged: 56.19 ± 10.05, 25% females) were included. 18 kDa-translocator protein positron emission tomography (TSPO-PET) with the 11C-PK11195 radioligand was used to measure neuroinflammatory activity. The Network Modification (NeMo) [6] tool was used to estimate how much each voxel in the WM was disrupted due to PRLs and non-PRLs, as detected on MRI. The NeMo Tool's estimated disruption is defined as the percent of tractography-defined streamlines passing through that voxel that also passes through the lesion mask. The tractography database consists of WM streamlines from 420 unrelated healthy controls (206 female, 214 male, 28.7 ± 3.7 years) from the Human Connectome Project Young Adult dataset. Expanded Disability Status Scale (EDSS) was used to measure disability in MS patients. The comparison of the inflammatory activity between the groups was performed via ANCOVA with age and sex as covariates. Associations between inflammatory activity and EDSS were performed using a linear model with age and sex as covariates.
Results:
MS patients had higher inflammatory activity in whole-brain WM compared to healthy controls (p=0.001). Patients with PRL exhibited higher levels of inflammatory activity in WM highly disrupted by MS lesions of any type compared to patients without PRLs (p=0.02) (See Figure 1). For the patients with at least one PRL, inflammatory activity was higher in WM highly disrupted by PRLs compared to non-PRLs (p=0.009). Elevated inflammatory activity in highly disrupted WM was associated with increased disability in patients with PRL (p=0.03), but not in patients without PRL (p=0.2) (See Figure 2).
·Figure 1
·Figure 2
Conclusions:
This study suggests that patients with PRLs may exhibit more diffuse WM inflammation and more inflammation in WM highly connected to PRLs. This increased inflammation in WM disrupted by PRLs could contribute to larger lesion volumes and faster disability progression. PRLs may serve as a biomarker for identifying patients with both focal and diffuse inflammation, guiding therapeutic interventions aimed at reducing inflammation and preventing progressive disability in MS.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
PET Modeling and Analysis 2
Keywords:
Computational Neuroscience
Degenerative Disease
Modeling
Positron Emission Tomography (PET)
Other - Multiple Sclerosis
1|2Indicates the priority used for review
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[2] Tozlu, C. et al. Structural disconnectivity from paramagnetic rim lesions is related to disability in multiple sclerosis. Brain Behav. 11, e2353 (2021).
[3] Tozlu, C. et al. The sequence of regional structural disconnectivity due to multiple sclerosis lesions. Brain Commun. 5, fcad332 (2023).
[4] Absinta, M. et al. Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions. J. Clin. Invest. 126, 2597–2609 (2016).
[5] Reeves, J. A. et al. Associations Between Paramagnetic Rim Lesion Evolution and Clinical and Radiologic Disease Progression in Persons With Multiple Sclerosis. Neurology 103, e210004 (2024).
[6] Kuceyeski, A., Maruta, J., Relkin, N. & Raj, A. The Network Modification (NeMo) Tool: Elucidating the Effect of White Matter Integrity Changes on Cortical and Subcortical Structural Connectivity. Brain Connect. 3, 451–463 (2013).