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

The research team, led by Alberto Fernández and Javier García-Alba of the Complutense University of Madrid, followed 57 adults with Down syndrome over a 24-month period. At the outset, participants were classified into three clinical groups based on their status along the Alzheimer’s disease continuum: 25 individuals were asymptomatic, 16 were in a prodromal stage, and 16 had already developed dementia. Each participant underwent clinical, neuropsychological, and biomarker assessments at baseline and again two years later, allowing the investigators to track how plasma levels of two key proteins changed over time and how those changes related to cognitive function.

The two biomarkers at the heart of the study were plasma neurofilament light chain, commonly abbreviated as NfL, and phosphorylated tau 217, or p-tau217. Neurofilament light is a structural protein released into the bloodstream when neurons are damaged, making it a general indicator of neurodegeneration. Phosphorylated tau 217, by contrast, is a form of the tau protein modified by the addition of phosphate groups, and it has emerged in recent years as one of the most specific blood markers of Alzheimer’s pathology, closely tracking the amyloid and tau deposits that define the disease in the brain.

The longitudinal design revealed a striking pattern: biomarker levels rose significantly over the two-year window only in the groups with pathological clinical status, that is, those classified as prodromal or demented. The steepest increases occurred in the dementia group, consistent with the idea that plasma markers of Alzheimer’s disease accelerate as the condition advances. Crucially, the asymptomatic group showed no comparable rise, suggesting that these blood measures remain relatively stable until the disease process has begun to manifest clinically.

Perhaps the most consequential finding concerned the predictive power of cognition. Among the neuropsychological measures collected at baseline, performance on the New Serial Learning Immediate test, or NSL-I, stood out as the strongest predictor of subsequent biomarker evolution. This test assesses episodic memory, the ability to encode and immediately recall new information, which is typically among the first cognitive domains affected by Alzheimer’s disease. The relationship was quantified precisely: each one-point increase in baseline NSL-I score was associated with a reduction of 0.035 units in the longitudinal increase of p-tau217 and a reduction of 0.463 units in the increase of NfL. In other words, better immediate memory performance at the start of the study foreshadowed slower accumulation of both Alzheimer-specific tau pathology and general neuronal injury over the following two years.

The clinical implications of this dose-response relationship are considerable. Because the NSL-I is a brief, low-cost assessment that can be administered in routine clinical settings, it could serve as an accessible screening tool to flag individuals with Down syndrome who are likely to experience rapid biomarker progression. This matters because diagnostic evaluation in this population has long been hampered by the absence of cognitive assessment instruments that are both sensitive to change and appropriately normed for people with intellectual disability. The study’s authors argue that episodic memory performance deserves a central place in monitoring protocols, not merely as a symptom to be catalogued but as an active predictor of the underlying biological trajectory.

Even more striking was the role of baseline p-tau217 in predicting clinical conversion. When the researchers examined which baseline measurements anticipated whether a participant would progress to a more advanced clinical stage during the follow-up period, only p-tau217 emerged as a significant predictor. Individuals whose baseline p-tau217 values were one unit above the sample median showed a 3.56-fold increased risk of clinical progression. This finding reinforces the growing consensus, reflected in recent diagnostic criteria from the Alzheimer’s Association and the International Working Group, that phosphorylated tau measured in plasma is not merely a correlate of disease but a genuine prognostic marker capable of identifying who will deteriorate before symptoms worsen.

The study builds on a rapidly expanding literature on blood-based biomarkers in Down syndrome. Because chromosome 21 carries the gene for amyloid precursor protein, people with Down syndrome have three copies of a key molecular ingredient of amyloid plaques, and virtually all of them develop the neuropathological hallmarks of Alzheimer’s disease by middle age. Previous cross-sectional work, including large studies published in The Lancet and Lancet Neurology, established that plasma p-tau217 and other markers can distinguish symptomatic from asymptomatic individuals with Down syndrome. What the new study adds is the temporal dimension: it demonstrates that these markers change measurably over just two years, that the rate of change depends on clinical status, and that both the rate of change and the risk of conversion can be anticipated from baseline measurements.

For clinicians and families, the practical message is twofold. First, a simple memory test can help identify which adults with Down syndrome are on a fast biological track, enabling closer monitoring and earlier access to care planning. Second, elevated plasma p-tau217 should be treated as a warning sign of impending clinical decline, warranting intensified follow-up. The authors explicitly frame their results as supporting the development of screening strategies to identify individuals at high risk of rapid cognitive decline and to inform the design of future therapeutic trials, where accurate stratification of participants is essential for detecting treatment effects.

There are, of course, limits to what a study of 57 participants followed for two years can establish, and the researchers note that larger and longer cohorts will be needed to confirm the findings and refine the predictive models. The datasets analyzed in the study are available from the corresponding author upon reasonable request under a data transfer agreement, and the work was supported by public funding from the Spanish Ministry of Science and Innovation. Still, the convergence of a brief cognitive measure and a specific blood protein into a coherent prognostic framework represents a meaningful step toward personalized risk assessment in Down syndrome, a population that has historically been excluded from the advances transforming Alzheimer’s care in the general population. As blood-based diagnostics move from research laboratories into routine practice, studies like this one help ensure that people with Down syndrome are not left behind.

Subject of Research: Longitudinal plasma biomarker and cognitive predictors of Alzheimer's disease progression in Down syndrome

Article Title: The link between plasma and cognitive markers for Alzheimer’s disease in Down syndrome: a longitudinal study

Article References: The link between plasma and cognitive markers for Alzheimer’s disease in Down syndrome: a longitudinal study. (n.d.). https://doi.org/10.1007/s00415-026-14165-6

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14165-6

Keywords: Down syndrome, Alzheimer's disease, p-tau217, neurofilament light, plasma biomarkers, episodic memory, longitudinal study, clinical conversion, dementia, neuropsychological testing, biomarker progression, Journal of Neurology