Age Rewrites the Brain Rules of Early Multiple Sclerosis, Five-Year Study Finds

Multiple sclerosis has long been framed as a disease of inflammatory flare-ups and white-matter scars, but one of its most disabling features is far quieter: cognitive decline. Slowed thinking, impaired memory, and eroded executive function can appear early, sometimes before a diagnosis is even confirmed, and they profoundly shape quality of life. Now a prospective five-year study following people from their very first demyelinating event has uncovered a striking twist in how these cognitive problems relate to the brain itself. The findings, published in Annals of Clinical and Translational Neurology, suggest that age does not merely add risk on top of the disease process. Instead, it fundamentally changes the relationship between cognition and brain structure, pointing toward a possible synergy between multiple sclerosis and the biology of brain aging.

The research team recruited participants within three months of a first clinical demyelinating event, often called a clinically isolated syndrome, at The National Hospital for Neurology and Neurosurgery and Moorfields Eye Hospital in London. Forty participants, averaging about 32 years of age at baseline and roughly two-thirds female, completed detailed clinical, cognitive, and magnetic resonance imaging assessments. Five years later, the same individuals returned for a comprehensive re-evaluation, giving researchers an unusually clean window into the earliest stages of the disease, before years of cumulative damage could muddy the picture.

Cognitive function was assessed with the Minimal Assessment of Cognitive Function in MS, a battery widely regarded as the gold standard for this population because it covers the domains most commonly affected, including processing speed, learning, memory, and executive function. Each participant’s raw scores were converted into standardized Z-scores using regression-based normative data, which already account for age, sex, and education. Using the conventional impairment threshold of Z below minus 1.50 on at least one subtest, 43 percent of the cohort met criteria for cognitive impairment at five years. When the researchers applied a more lenient cutoff of Z below minus 1.00, designed to capture subtler dysfunction on the continuum between normal cognition and frank impairment, the figure rose to 53 percent.

The pattern of deficits was revealing. The most frequently failed tests were the Controlled Oral Word Association Test, a measure of phonemic verbal fluency, and the Delis-Kaplan Executive Function System Sorting Test, specifically its Description Score, which demands abstraction, concept formation, and cognitive flexibility. By contrast, failures on the Symbol Digit Modalities Test, the workhorse screening measure of processing speed, were almost absent. The authors argue that larger MS cohorts may systematically underestimate executive dysfunction because brief screening batteries lack dedicated executive measures, whereas the fuller MACFIMS battery is far more sensitive to these higher-order deficits, which can emerge even when processing speed appears intact.

On the imaging side, the team acquired high-resolution three-dimensional T1-weighted and FLAIR sequences on a 3 Tesla scanner and used an automated lesion segmentation pipeline, manually quality-checked, to quantify lesion counts and lesion volumes. Brain tissue volumes, including gray matter, white matter, and total intracranial volume, were derived after lesion filling, a computational step that prevents lesions from distorting tissue segmentation. All volumetric analyses were adjusted for head size. The central question was simple but important: which MRI measures, five years after the first demyelinating event, predicted who had developed cognitive impairment, and did age modify those relationships?

The answer centered on gray matter. In models adjusted for total intracranial volume alone, each cubic centimeter decrease in gray matter volume was associated with roughly a 6 percent increase in the odds of cognitive impairment, an effect that held at both the conventional and lenient Z-score thresholds. Cortical gray matter showed a similar association, while white matter volume, lesion counts, and lesion volumes did not independently predict cognitive outcomes. Notably, when age and sex were added to the models, the MRI associations lost statistical significance, a hint that age was entangled with the gray matter story in a way that simple additive models could not capture.

That entanglement became explicit when the researchers tested interaction effects. Among participants classified as cognitively impaired at five years, each additional year of age was associated with roughly one cubic centimeter less gray matter, a significant negative slope. Among those who remained cognitively preserved, age had no measurable relationship with gray matter volume at all. In other words, the brains of cognitively impaired participants appeared to be aging faster, or at least shrinking faster, than the brains of their cognitively intact peers, even though the cognitive scores themselves had already been adjusted for age through the normative data.

Marginal contrast analyses sharpened the picture further. Below the age of 39, gray matter volumes did not differ meaningfully between cognitively impaired and cognitively preserved participants. Above that threshold, the groups diverged, with statistically significant differences emerging at age 39 and widening thereafter. Comparing modeled gray matter volume at age 25 versus age 45 within the cognitively impaired group revealed a difference of roughly 16 cubic centimeters, while no comparable age-related difference existed among those who stayed cognitively intact. The authors interpret this as a possible synergistic effect between brain aging and disease-related gray matter loss, speculating that diminished gray matter reserve may modulate MS-related cognitive outcomes as people get older. This resonates with a growing literature on accelerated or premature brain aging in MS, often quantified through brain-age modeling, in which MRI-derived estimates of brain age exceed chronological age in people with the disease.

Importantly, the cognitive outcomes were not explained by the usual clinical suspects. Post hoc analyses found no associations between cognitive impairment and disease-modifying therapy use or type, steroid treatment, relapse frequency, fatigue, or anxiety and depression. This absence of association underscores that the gray matter and age effects were not simply proxies for more relapses or more aggressive inflammatory treatment histories, and it reinforces the idea that neurodegenerative processes, unfolding quietly and independently of visible relapse activity, may drive early cognitive change. That aligns with accumulating evidence that progression independent of relapse activity can begin insidiously, even before the first clinical event.

The study has honest limitations. Forty participants is a small sample, which may explain why only gray matter measures reached significance, and the authors caution that the absence of associations with deep gray matter or lesion measures should not be read as evidence of absence. The cohort was also dominated by optic neuritis as the presenting event, and there was no healthy control group. The magnitude of the gray matter differences, while statistically robust, raises questions about biological meaningfulness that only longer follow-up can answer. Still, the core message stands and carries practical weight: cognitive assessment, particularly of executive function, deserves a place in routine early MS care, and age may be a critical variable in identifying who is most vulnerable. Future longitudinal studies, ideally beginning even before the first demyelinating event in people with radiologically isolated syndromes, could clarify whether protecting gray matter reserve in early adulthood offers a genuine buffer against the cognitive toll of multiple sclerosis decades later.

Subject of Research: Age-related modulation of the association between cognitive impairment and gray matter brain volumes in the five years following a first demyelinating event in multiple sclerosis

Article Title: Advancing Age Modulates Associations Between Cognitive Impairment and Brain Volumes in Early MS

Article References: Ananthavarathan, P., Pitteri, M., Foster, M., Collorone, S., Salama, S., Colato, E., Prados, F., Kanber, B., Yiannakas, M., Gandini Wheeler‐Kingshott, C. A. M., Davagnanam, I., Barkhof, F., Chard, D., Ciccarelli, O., & Toosy, A. (2026). Advancing Age Modulates Associations Between Cognitive Impairment and Brain Volumes in Early MS. Annals of Clinical and Translational Neurology, 13(10), 2124-2133. https://doi.org/10.1002/acn3.70385

Image Credits: AI Generated

DOI: 10.1002/acn3.70385

Keywords: multiple sclerosis, cognitive impairment, gray matter volume, brain aging, MRI, clinically isolated syndrome, executive function, MACFIMS, neurodegeneration, brain-age paradigm, demyelinating event, longitudinal study