Mediation Analysis Between Brain Age, Disease-Modifying Factors, and Disability and Cognitive Performance in Multiple Sclerosis.

Abstract (English)

BACKGROUND AND OBJECTIVES: The brain-predicted age difference (brain-PAD) is considered a marker of neurodegeneration in people with multiple sclerosis (pwMS) and is associated with greater disability and cognitive impairment. However, the impact of disease-modifying factors (DMFs) on brain-PAD remains unknown, as does the extent to which their effect on disability and cognition is mediated through brain-PAD. The goal of this study was to investigate this in pwMS using a same-age cohort to eliminate calendar age as a confounding factor. METHODS: Brain age was determined using brainageR from 3-dimensional T1-weighted MRI scans, and brain-PAD was calculated as the difference between predicted and chronological age. Disability was evaluated with the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9HPT), and timed 25-foot walk test (T25FWT). Cognitive function was assessed using the Minimal Assessment of Cognitive Function in MS battery and converted to <i>Z</i>-scores. DMFs included lifetime smoking, alcohol consumption, physical activity, diet, leisure, and educational level, as well as body mass index (BMI) at 18 years. The effect of DMFs on brain-PAD was examined using linear regression, adjusting for sex. Mediation analyses were performed to investigate to what extent brain-PAD is a mediator of DMF effects on disability and cognition. RESULTS: The study included 117 healthy controls (mean age 52.8 &#xb1; 1.1 years, 74.3% female) and 242 pwMS (mean age 52.8 &#xb1; 0.9 years, 70.6% female), with a median disease duration of 15.2 years (interquartile range [IQR] 8.2-24.5) and a median EDSS score of 3.5 (IQR 2.5-4.0). Smoking (&#x3b2; = 0.20, <i>p</i> = 0.002), alcohol consumption (&#x3b2; = 0.18, <i>p</i> = 0.007), and BMI at 18 years (&#x3b2; = 0.15, <i>p</i> = 0.021) were associated with a higher brain-PAD, whereas higher physical activity (&#x3b2; = -0.13, <i>p</i> = 0.041) was linked to a lower brain-PAD. Mediation analysis demonstrated an indirect effect of smoking and alcohol on EDSS score (&#x3b2; = 0.039, <i>p</i> = 0.003; &#x3b2; = 0.039, <i>p</i> = 0.009), 9HPT (&#x3b2; = 0.057, <i>p</i> < 0.0001; &#x3b2; = 0.055, <i>p</i> = 0.004), T25FWT score (&#x3b2; = 0.045, <i>p</i> = 0.009; &#x3b2; = 0.044, <i>p</i> = 0.013), and cognitive performance (&#x3b2; = -0.066, <i>p</i> = 0.0004; &#x3b2; = -0.060, <i>p</i> = 0.016). Physical activity demonstrated an indirect effect of better performance on EDSS score (&#x3b2; = -0.027, <i>p</i> = 0.032) and cognitive performance (&#x3b2; = 0.042, <i>p</i> = 0.034). DISCUSSION: DMFs unrelated to MS, particularly smoking, alcohol use, and BMI at 18 years, accelerate brain aging. Brain-PAD mediates these effects and contributes to worsening disability and cognition, underscoring the potential of lifestyle interventions to mitigate neurodegeneration and preserve function in pwMS.