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Peer-reviewedCC BYBrain communications

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

  • Nicolò Tedone1,2
  • Paola Valsasina1
  • Alessandro Meani1
  • Paolo Preziosa1,2,3
  • Marta Grosselle1
  • Federica Esposito3
  • Massimo Filippi1,2,3,4,5
  • Maria A Rocca1,2,3
5 affiliations
  1. 1Neuroimaging Research Unit, Institute of Experimental Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  2. 2Vita-Salute San Raffaele University, 20132 Milan, Italy.
  3. 3Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  4. 4Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  5. 5Neurophysiology Service, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
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Abstract

Functional network reorganization supports compensatory mechanisms in multiple sclerosis, but ageing 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 10 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) and 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 is related to lower normalized brain volume and worse cognition (P = 0.02-0.03), whereas altered thalamic network connectivity is 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.

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Cite

BibTeXRIS
BibTeX
@article{tedone2026advanced,
  title = {{Advanced age at onset is associated with distinct functional brain reorganization in multiple sclerosis.}},
  author = {Nicolò Tedone and Paola Valsasina and Alessandro Meani and Paolo Preziosa and Marta Grosselle and Federica Esposito and Massimo Filippi and Maria A Rocca},
  journal = {Brain communications},
  year = {2026},
  month = oct,
  doi = {10.1093/braincomms/fcag396},
  url = {https://europepmc.org/article/MED/42953422},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Advanced age at onset is associated with distinct functional brain reorganization in multiple sclerosis.
AU  - Nicolò Tedone
AU  - Paola Valsasina
AU  - Alessandro Meani
AU  - Paolo Preziosa
AU  - Marta Grosselle
AU  - Federica Esposito
AU  - Massimo Filippi
AU  - Maria A Rocca
PY  - 2026
DA  - 2026/10/16
JO  - Brain communications
DO  - 10.1093/braincomms/fcag396
UR  - https://europepmc.org/article/MED/42953422
AB  - Functional network reorganization supports compensatory mechanisms in multiple sclerosis, but ageing 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 10 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) and 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 is related to lower normalized brain volume and worse cognition (P = 0.02-0.03), whereas altered thalamic network connectivity is 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.
SN  - 2632-1297
ER  -