Silent Brain Scars Predict Cognitive Decline in Early Multiple Sclerosis

Multiple sclerosis has long been framed as a disease of dramatic attacks: sudden episodes of blurred vision, numbness, or weakness that announce the immune system’s assault on the central nervous system. But a growing body of research suggests that the most consequential damage often unfolds in silence, beneath the radar of both clinical relapses and conventional MRI scans. A new longitudinal study published in Annals of Clinical and Translational Neurology now offers some of the strongest evidence yet that two specific imaging signatures, visible at the moment of diagnosis, can foreshadow years of quiet cognitive deterioration in people with early relapsing–remitting multiple sclerosis.

The research, conducted on 87 patients enrolled prospectively at the time of their diagnosis, focused on a phenomenon that neurologists call cognitive PIRMA: progression independent of relapse and MRI activity. In plain terms, this is cognitive decline that occurs without any accompanying flare-up of disease and without the appearance of new inflammatory lesions on standard brain imaging. It belongs to a broader family of insidious worsening known as progression independent of relapse activity, or PIRA, which is increasingly recognized as the dominant driver of long-term disability in multiple sclerosis. The biological engine behind PIRA is thought to be so-called smoldering inflammation, a compartmentalized, chronic inflammatory process that grinds away at neurons and their axons inside the brain without triggering the visible alarms that clinicians routinely monitor.

The scale of the problem revealed by the study is striking. Over a mean follow-up of roughly six years, 55 of the 87 patients, or 63.2 percent, experienced meaningful cognitive decline as measured by validated neuropsychological tests. Of those, the overwhelming majority, 44 patients or 80 percent, declined without any temporally associated relapse or MRI activity, qualifying as cognitive PIRMA. Only eight patients had decline linked to a relapse, and just three showed concurrent MRI activity. In other words, when cognition worsened in this early-stage cohort, it almost never did so because of an obvious inflammatory event. The damage was happening off-screen.

Capturing this silent decline required unusually rigorous methodology. The researchers administered a comprehensive battery of neuropsychological tests at diagnosis and at intervals of at least a year thereafter, including the Symbol Digit Modalities Test, the Brief Visuospatial Memory Test-Revised, and the Paced Auditory Serial Addition Task. To distinguish genuine deterioration from ordinary measurement noise or practice effects, they applied the Reliable Change Index, a conservative statistical threshold that accounts for the inherent variability of repeated testing. To classify a decline as cognitive PIRMA, the team demanded an 18-month window of freedom from disease activity, spanning nine months before and after the cognitive worsening, a far stricter criterion than the conventional three-month window used in much of the field. Any relapse within that interval reclassified the event as relapse-associated worsening.

With that framework in place, the researchers turned to two candidate MRI markers of smoldering inflammation, both measured on 3 Tesla scans at diagnosis. The first was the paramagnetic rim lesion, or PRL, a chronic active lesion whose edge is rimmed by iron-laden microglia and macrophages, rendering it visible on susceptibility-weighted phase images as a dark rim. These lesions are found in roughly half of all MS patients and are considered a highly specific hallmark of persistent, compartmentalized inflammation. Their clinical weight has grown to the point that the 2024 revisions of the MS diagnostic criteria now include them as supportive evidence. The second marker was the choroid plexus, the tufted structure in each brain ventricle that produces cerebrospinal fluid and forms an immunologically active blood–CSF barrier. An enlarged choroid plexus is thought to reflect immune cell trafficking and sustained inflammatory activation at this gateway between blood and brain.

The results were consistent for both markers. Patients who went on to develop cognitive PIRMA had significantly more paramagnetic rim lesions at diagnosis than those who remained cognitively stable, with a median of 1.5 lesions versus 1.0, a difference that held after correction for multiple comparisons. Even more telling, 85.3 percent of the future decliners had at least one PRL, compared with 52.0 percent of the cognitively stable group, a difference that was highly significant. Notably, the overall burden of conventional white matter lesions did not differ between the groups, suggesting that it is the biology of the lesions, not their sheer number, that matters for cognition. Choroid plexus volume, normalized for total intracranial volume, was likewise significantly larger in the decliners, at 0.18 percent versus 0.16 percent of intracranial volume.

Regression analyses sharpened the picture further. In a multivariable logistic regression adjusting for baseline age, sex, disability score, treatment exposure, follow-up duration, and lesion burden, the mere presence of at least one paramagnetic rim lesion emerged as the only statistically significant predictor of subsequent cognitive PIRMA, with an odds ratio of 5.2 and a model area under the receiver operating characteristic curve of 0.80, indicating good discriminative ability. Choroid plexus volume performed similarly, with an odds ratio of 5.1 and an AUC of 0.77 in its adjusted model. Interestingly, the presence or absence of rim lesions predicted outcome better than the exact count of lesions, a practical finding, since counting PRLs reliably requires specialized image processing that many MS centers cannot easily perform, whereas detecting whether any exist is more feasible.

The biological story these markers tell is coherent. At the rim of chronic active lesions, microglia and macrophages remain persistently activated, slowly stripping away myelin and severing axons in a zone of smoldering injury that standard gadolinium-enhanced MRI never flags. Meanwhile, a dysfunctional or inflamed choroid plexus may sustain the proinflammatory milieu by facilitating ongoing immune cell entry into the central nervous system, a mechanism supported by neuropathological and cerebrospinal fluid studies in progressive MS. Together, these processes could quietly erode the neural substrate of processing speed, memory, and executive function long before physical disability becomes apparent, explaining why cognitive decline in this cohort was largely disconnected from relapses, lesion accumulation, and even baseline cognitive status, which did not differ significantly between the groups.

The clinical implications are considerable. Cognitive impairment is among the most disabling manifestations of multiple sclerosis, eroding employment, independence, and quality of life, yet it is rarely monitored with the same rigor as walking or relapse frequency. If a routine diagnostic scan could flag patients at high risk of silent cognitive decline, clinicians might stratify treatment intensity earlier, monitor cognition more closely, and eventually target the smoldering pathways themselves, several of which are already in the crosshairs of experimental therapies. The authors caution that their findings are preliminary: the sample was modest, the follow-up limited, and the interval between cognitive assessments constrained temporal precision. Future work will need to confirm decline over time, relate these markers to physical PIRA, and test whether rim lesions and choroid plexus volume act synergistically when combined in a single multiparametric model. Still, the message is clear: the seeds of silent cognitive decline in multiple sclerosis may be sown at diagnosis, and the tools to see them are already on the scanner.

Subject of Research: MRI markers of smoldering inflammation predicting cognitive progression in early relapsing–remitting multiple sclerosis

Article Title: Paramagnetic Rim Lesions and Choroid Plexus Volume at Diagnosis Are Associated With Cognitive Progression Independent of Relapse and MRI Activity in Early Relapsing–Remitting Multiple Sclerosis

Article References: Ziccardi, S., Marastoni, D., Tamanti, A., Biasi, P., Visani, V., Colombi, A., Fuchs, T. A., Sicchieri, M., Eccher, C., Guarnaccia, F., Calderone, M., Camera, V., Pizzini, F. B., Magliozzi, R., Castellaro, M., & Calabrese, M. (2026). Paramagnetic Rim Lesions and Choroid Plexus Volume at Diagnosis Are Associated With Cognitive Progression Independent of Relapse and MRI Activity in Early Relapsing–Remitting Multiple Sclerosis. Annals of Clinical and Translational Neurology, 13(10), 2154-2160. https://doi.org/10.1002/acn3.70448

Image Credits: AI Generated

DOI: 10.1002/acn3.70448

Keywords: multiple sclerosis, paramagnetic rim lesions, choroid plexus, cognitive decline, PIRMA, smoldering inflammation, MRI biomarkers, relapsing-remitting MS, neuroinflammation, PIRA, neuropsychological testing, brain atrophy