Worse Physical Disability Is Associated With the Expression of PD-1 on Inflammatory T-Cells in Multiple Sclerosis Patients With Older Appearing Brains

Abstract

Background: Magnetic Resonance Imaging (MRI) analysis method “brain-age” paradigm could offer an intuitive prognostic metric (brain-predicted age difference: brain-PAD) for disability in Multiple Sclerosis (MS), reflecting structural brain health adjusted for aging. Equally, cellular senescence has been reported in MS using T-cell biomarker CD8+CD57+.Objective: Here we explored links between MRI-derived brain-age and blood-derived cellular senescence. We examined the value of combining brain-PAD with CD8+CD57+(ILT2+PD-1+) T-cells when predicting disability score in MS and considered whether age-related biological mechanisms drive disability.Methods: Brain-age analysis was applied to T1-weighted MRI images. Disability was assessed and peripheral blood was examined for CD8+CD57+ T-cell phenotypes. Linear regression models were used, adjusted for sex, age and normalized brain volume.Results: We included 179 mainly relapsing-remitting MS patients. A high brain-PAD was associated with high physical disability (mean brain-PAD = +6.54 [5.12–7.95]). CD8+CD57+(ILT2+PD-1+) T-cell frequency was neither associated with disability nor with brain-PAD. Physical disability was predicted by the interaction between brain-PAD and CD8+CD57+ILT2+PD-1+ T-cell frequency (AR2 = 0.196), yet without improvement compared to brain-PAD alone (AR2 = 0.206; AICc = 1.8).Conclusion: Higher frequency of CD8+CD57+ILT2+PD-1+ T-cells in the peripheral blood in patients with an older appearing brain was associated with worse disability scores, suggesting a role of these cells in the development of disability in MS patients with poorer brain health.

Confounder-adjusted MRI-based predictors of multiple sclerosis disability

“…Magnetic resonance imaging (MRI) volumetric outcomes such as brain atrophy, have been successfully used in Phase II and Phase III MS clinical trials (2)(3)(4). However, is brain atrophy the most sensitive and the most specific imaging outcome in MS?…”

“…The logical extension of this alternative interpretation is that aging and other physiological confounding effects on brain MRI volumes represent “noise” when measuring MS-specific processes. Here, we examine this hypothesis by addressing the following aims: (1) To adjust volumes of the CNS structures for physiological confounders to understand MS-specific effects on CNS structures; (2) To examine, whether confounder-adjusted MRI predictors can be assembled into models that predict clinical disability in the independent validation cohort, and whether such model(s) exerts larger effect size(s) than any single MRI biomarker; ( 3 ) To investigate whether computational model(s) derived from confounder-adjusted MRI predictors outperform models(s) from raw MRI volumes in predicting clinical disability outcomes.…”

Confounder-adjusted MRI-based predictors of multiple sclerosis disability

“…Magnetic resonance imaging (MRI) volumetric outcomes such as brain atrophy, have been successfully used in Phase II and Phase III MS clinical trials (Hemond and Bakshi, 2018; Jacobs et al, 2021; Zeydan and Kantarci, 2020). However, is brain atrophy the most sensitive and the most specific imaging outcome in MS?…”