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 (AR ² = 0.196), yet without improvement compared to brain-PAD alone (AR ² = 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.

Keywords: MRI; atrophy; biomarkers; brain age; immunology; multiple sclerosis.