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Advanced age at onset is associated with distinct functional brain reorganization in multiple sclerosis

Year: 2026

Type: article

Abstract: Functional network reorganization supports compensatory mechanisms in multiple sclerosis, but aging and later disease onset may alter this balance. Late-onset multiple sclerosis (age at onset ≥50 years) represents a relevant subgroup to examine how disease onset in older age is associated with functional connectivity abnormalities. In this cross-sectional study, we investigated resting-state functional connectivity alterations in late-onset multiple sclerosis versus adult-onset multiple sclerosis and their associations with clinical, cognitive, and structural MRI measures. Thirty-four late-onset multiple sclerosis, 169 sex- and disease duration–matched adult-onset multiple sclerosis, and 163 age- and sex-matched healthy controls underwent clinical, neuropsychological (Brief Repeatable Battery of Neuropsychological Tests), and MRI assessment including resting-state functional MRI. Independent component analysis quantified resting-state functional connectivity within ten large-scale networks. Between-group differences were tested using sex- and scanner-adjusted voxel-wise models (p<0.001, uncorrected, cluster extent ≥10 voxels); resulting abnormal clusters were then examined for exploratory uncorrected associations with Expanded Disability Status Scale, disease duration, cognitive performance, T2-hyperintense lesion volume, and normalized brain volume, without correction for multiple comparisons. At MRI acquisition, compared with the adult-onset multiple sclerosis group, the late-onset multiple sclerosis group was significantly older (median age: 60.5 [IQR: 56.6–66.1] versus 35.6 [IQR: 30.0–40.1] years; pFDR=0.006), showed higher Expanded Disability Status Scale score (pFDR=0.016) and higher T2-hyperintense lesion volume (pFDR=0.028) despite similar disease duration (median: 4.5 [IQR: 1.7–13.2] versus 6.0 [IQR: 2.1–11.8] years; pFDR=0.894), whereas no significant between-group cognitive difference was found. Both multiple sclerosis groups showed widespread functional connectivity abnormalities versus healthy controls, partly overlapping and partly distinct. Adult-onset multiple sclerosis displayed functional connectivity increases in the executive control and occipital default mode networks. Late-onset multiple sclerosis showed diffuse functional connectivity alterations, including decreases in the left fronto-parietal, thalamic, and occipital default mode networks. Exploratory uncorrected correlation analyses included 117 tested associations. In late-onset multiple sclerosis, decreased functional connectivity in the left fronto-parietal network related to lower normalized brain volume and worse cognition (p=0.02–0.03), whereas altered thalamic network connectivity related to higher Expanded Disability Status Scale, longer disease duration, and higher T2-hyperintense lesion volume (p=0.01-0.02). These associations did not survive correction for multiple comparisons and should therefore be considered hypothesis-generating. These findings suggest that late-onset multiple sclerosis was associated with a distinct resting-state functional connectivity profile compared with adult-onset multiple sclerosis within a cross-sectional, age-matched healthy control framework, possibly reflecting the combined contribution of multiple sclerosis-related damage, age-related vulnerability, and the more severe clinical profile of late-onset multiple sclerosis.

Source: Brain Communications

DOI: 10.1093/braincomms/fcag396