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

Cerebral small vessel disease, often abbreviated CSVD, is a collection of changes in the brain’s tiniest blood vessels. It shows up on MRI scans as white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and other subtle markers. Individually, these changes often cause no noticeable problems, which is why researchers sometimes call the condition occult, meaning hidden. But epidemiological studies have linked CSVD to cognitive decline, gait problems, and stroke. When it occurs alongside type 2 diabetes, a metabolic disorder that already damages blood vessels throughout the body, the risk of severe cognitive impairment rises sharply. The question the Chinese team set out to answer was whether modern imaging could detect the earliest functional consequences of that combination, before patients or their families notice anything wrong.

The study took a retrospective approach, analyzing the records of patients with type 2 diabetes who had been hospitalized in the Endocrinology Department between November 2024 and November 2025. Using magnetic resonance imaging, the researchers divided the patients into two groups: those with signs of cerebral small vessel disease and those without. For every participant, they collected laboratory indicators of glucose metabolism, lipid metabolism, and liver and kidney function, alongside both structural and functional MRI. This pairing of blood chemistry with brain imaging is what makes the study particularly valuable, because it allowed the investigators to connect metabolic control directly to measurable changes in brain structure and connectivity.

The first major finding concerned glycated hemoglobin, or HbA1c, the standard long-term measure of blood sugar control that reflects average glucose levels over the preceding two to three months. Through statistical modeling, the team found that HbA1c was an independent risk factor for the occurrence of cerebral small vessel disease in diabetes patients, with an odds ratio of 1.7 and a p-value of 0.038. In practical terms, this means that each increment in HbA1c raises the odds of developing CSVD by roughly seventy percent, independent of other measured factors. For clinicians, the message is straightforward: sustained poor glycemic control is not just a risk for the eyes, kidneys, and heart, but for the brain’s smallest vessels as well.

Next, the researchers turned to diffusion tensor imaging, or DTI, a technique that tracks the movement of water molecules through brain tissue. In the orderly cables of white matter that connect distant brain regions, water diffuses preferentially along the direction of the nerve fibers. When those fibers are damaged or disorganized, the diffusion pattern changes in measurable ways. The team focused on two metrics: mean diffusivity, which measures the overall freedom of water movement, and the anisotropy mode, which describes the shape of the diffusion pattern and can distinguish between different types of tissue damage. In patients with both diabetes and CSVD, the mean diffusivity values in the right middle cingulum, a major fiber bundle running through the cingulate cortex that is involved in attention, emotion, and cognitive control, were significantly higher than in diabetes patients without CSVD, with a p-value of 0.036. The anisotropy mode values in the same region were closer to zero, a pattern that suggests the tissue microstructure there has been altered in a way consistent with vascular injury.

The second half of the investigation used resting-state functional MRI, which measures spontaneous fluctuations in blood oxygen levels while the subject simply lies still in the scanner. Regions that fluctuate together are considered functionally connected, forming networks that underpin memory, attention, and self-referential thought. The researchers placed seed points in the cingulum and the hippocampus, the brain’s principal memory-forming structure, and then performed voxel-wise functional connectivity analysis across the whole brain. The results were striking. Patients with diabetes and CSVD showed significantly reduced functional connectivity in the hippocampus, the parahippocampal region, and the prefrontal cortex, with corrected p-values below 0.001. These are precisely the regions that house the default mode network and the medial temporal memory system, and their disruption is a well-recognized signature of early cognitive decline.

When the team narrowed the analysis to specific regions of interest, the pattern held. The z-transformed functional connectivity values of the left hippocampus and of the edge memory circuit were significantly decreased in the diabetes-plus-CSVD group, at p-values below 0.05. The hippocampus is exquisitely vulnerable to both vascular injury and metabolic stress, and reduced connectivity between the hippocampus and cortical regions is one of the earliest imaging signs of memory impairment. The fact that these changes appeared in patients who were hospitalized for diabetes management, not for dementia, underscores how early in the disease process the brain’s networks can be affected.

Perhaps the most intriguing result came from the correlation analysis. The researchers examined how the imaging measures related to laboratory indicators, and found that in patients with diabetes and CSVD, the strongest association was with glycosylated albumin, a shorter-term marker of glucose fluctuation, with a correlation coefficient of -0.681 and a p-value of 0.010. The negative sign indicates that higher levels of glycosylated albumin were associated with lower values of the connectivity measure. Unlike HbA1c, which averages glucose over months, glycosylated albumin reflects glucose control over roughly two to three weeks, making it sensitive to day-to-day swings. This suggests that glucose variability, not just average glucose, may be particularly damaging to the functional organization of the brain in patients whose small vessels are already compromised.

Taken together, the study’s findings sketch a coherent biological story. Chronic hyperglycemia, reflected in elevated HbA1c, independently increases the risk that a person with type 2 diabetes will develop cerebral small vessel disease. Once the small vessels are damaged, the brain’s white matter begins to deteriorate, as shown by the elevated mean diffusivity in the cingulum. That structural damage then cascades into functional disruption, weakening the communication between the hippocampus, the parahippocampal cortex, and the prefrontal regions that together support memory and cognition. The correlation with glycosylated albumin adds a further layer, hinting that glycemic fluctuation accelerates this functional decline. The authors conclude that the combination of diffusion tensor imaging and resting-state functional MRI can serve as an early imaging biomarker for occult brain cognitive impairment in patients with diabetes combined with CSVD.

The implications reach beyond the radiology suite. If HbA1c is an independent and modifiable risk factor, then aggressive glycemic control in diabetes patients could plausibly reduce the incidence of cerebral small vessel disease and, by extension, protect the brain’s memory circuits. And if multimodal MRI can detect functional decline before symptoms emerge, clinicians could in principle identify high-risk patients and intervene earlier, whether through tighter metabolic management, vascular risk factor control, or closer cognitive monitoring. The study is not without limitations inherent to its retrospective, single-center design, and the authors note that the published version is an early-release article subject to further edits. Still, the work represents a meaningful step toward making the invisible visible: using physics-based imaging to catch the quiet, cumulative damage that diabetes inflicts on the brain’s smallest vessels and the networks they sustain, years before memory begins to fail.

Subject of Research: Altered brain functional connectivity and white matter microstructure in type 2 diabetes with and without cerebral small vessel disease, assessed with multimodal MRI

Article Title: Altered functional connectivity in type 2 diabetes with and without cerebral small vessel disease: a multimodal MRI study

Article References: Zheng, L., Wang, M., Lin, X., & Xue, Y. (2026). Altered functional connectivity in type 2 diabetes with and without cerebral small vessel disease: a multimodal MRI study. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02890-3

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02890-3

Keywords: type 2 diabetes, cerebral small vessel disease, functional connectivity, diffusion tensor imaging, resting-state fMRI, hippocampus, HbA1c, white matter, cingulum, cognitive impairment, glycated albumin, MRI biomarkers

A new study published in the Journal of Neurology by Dejan Jakimovski of the University of Rochester and the University at Buffalo, together with an international team of collaborators, tackles that question head-on, and its answer is striking. The researchers found that prolonged P100 latency is directly and independently associated with hallmark MRI signatures of neurodegeneration in multiple sclerosis, including reduced whole brain volume, reduced gray matter volume, and a heavier burden of T2-FLAIR lesions. Critically, these associations persisted even after the team statistically accounted for retinal structural damage and for age, two factors that could otherwise explain the link. The work suggests that a humble electrophysiological measurement of visual processing speed may function as a window onto the diffuse neurodegenerative processes quietly reshaping the brain.

The central methodological challenge the investigators faced was one of disentanglement. Shifts in P100 latency could, in principle, arise from changes anywhere along the visual pathway. Upstream, at the level of the retina, loss of retinal ganglion cell axons, measurable as thinning of the peripapillary retinal nerve fiber layer, could plausibly slow the signal before it even reaches the optic nerve. Downstream, widespread damage within the brain, including demyelination of visual radiations and atrophy of cortical and subcortical structures, could equally delay the arrival of the evoked response. Without a way to separate these possibilities, the interpretation of a delayed P100 wave remained ambiguous. A delayed signal might simply be a retinal story told in milliseconds.

To resolve this ambiguity, the team enrolled 64 people with multiple sclerosis and subjected each participant to a trio of complementary assessments. Spectral domain optical coherence tomography, performed on Heidelberg Spectralis hardware, provided precise measurements of peripapillary retinal nerve fiber layer thickness, an established structural proxy for retinal axonal integrity. Standardized VEP testing yielded monocular P100 latency values for each eye, capturing the functional speed of signal conduction through the visual system. Finally, magnetic resonance imaging delivered quantitative measures of whole brain volume, gray matter volume, and T2-FLAIR lesion volume, the canonical MRI outcomes that neurologists use to gauge tissue destruction and disease progression.

The analytical centerpiece of the study was a series of mediation analyses, a statistical framework that allows researchers to ask whether the relationship between two variables persists after accounting for a third variable that might lie on the causal path between them. In this case, the investigators modeled whether the association between P100 latency and MRI outcomes was mediated by retinal nerve fiber layer thickness, while also adjusting for the well-known effect of age on brain volume. If retinal thinning were the true driver, then once it was held constant, the connection between VEP latency and brain atrophy should have evaporated. It did not.

The results were unambiguous. P100 latency was significantly associated with lower whole brain volume, with a p-value of 0.0037, and remarkably, 87.8 percent of that total effect proved to be direct and independent of both retinal nerve fiber layer measures and the significant age-related covariate effect on brain volume. In other words, nearly nine-tenths of the relationship between slowed visual conduction and brain shrinkage could not be explained by retinal damage or the passage of time. The pattern extended to the other MRI outcomes as well: greater P100 latency directly and independently predicted lower gray matter volume, with p equal to 0.015, and greater T2-FLAIR lesion volume, with p equal to 0.0036, after adjustment for the mediating effects of retinal thickness and age.

These findings carry weight because they reposition the VEP from a narrow diagnostic tool to something approaching a whole-nervous-system barometer. The P100 latency, long appreciated for its role in detecting subclinical optic nerve involvement and in supporting diagnosis under frameworks such as the McDonald criteria, now shows age- and retinal-independent associations with the very imaging outcomes that define neurodegeneration in multiple sclerosis. The authors suggest that, in addition to their established diagnostic utility, VEP measures may provide an objective neurophysiological metric for assessing neurodegeneration itself, a prospect with obvious appeal for clinical trials of remyelinating and neuroprotective agents, where sensitive, repeatable, and inexpensive outcome measures are perpetually in demand.

The study did not emerge from a vacuum. Prior work by overlapping teams had already hinted that VEP latency carries prognostic significance beyond the optic nerve. Earlier investigations linked prolonged latency to longitudinal worsening of fatigue in people with multiple sclerosis and to variance in cognitive performance, while other analyses associated VEP latency measures with brain tissue volume differences and with cortical thinning attributed to trans-synaptic degeneration following optic neuritis. Longitudinal cohort studies had likewise proposed VEP as a prognostic biomarker for neuroaxonal damage, and historical analyses had explored its potential as an outcome measure for remyelination trials, building on observations that latency can recover slowly over years as remyelination proceeds after optic neuritis. The new mediation analysis strengthens this literature by rigorously excluding retinal structural change as an alternative explanation for the latency-brain association.

The interplay between optical coherence tomography and VEP is itself a story of complementary technologies converging on the same biology. OCT offers a structural readout, quantifying the physical thinning of the nerve fiber layer as axons are lost, and has been incorporated into the 2024 McDonald diagnostic criteria for multiple sclerosis alongside VEP. VEP offers a functional readout, capturing conduction speed through myelinated pathways, which can be prolonged by demyelination even when axonal architecture remains partially intact. By combining both modalities in a single cohort and formally testing mediation, the researchers could demonstrate that the functional signal conveys information about global brain health that the structural measurement alone does not capture, a distinction with real consequences for how clinicians and trialists interpret these tests.

Certain caveats temper the enthusiasm. The study was a retrospective analysis of de-identified clinical data, approved under exemption criteria with a waiver of informed consent, and its sample of 64 participants, while adequate for the mediation analyses performed, is modest by the standards of biomarker validation. The datasets are not publicly available due to institutional restrictions, though de-identified data may be shared with qualified researchers upon reasonable request. The cross-sectional design, relating latency to MRI outcomes measured at the same time, cannot establish the temporal precedence needed to declare VEP latency a true predictive biomarker of future atrophy rather than a concurrent correlate. Longitudinal confirmation in larger, independent cohorts will be essential before P100 latency earns a place alongside MRI volumetry in monitoring algorithms. Nevertheless, the prospect is tantalizing: a noninvasive, relatively inexpensive electrophysiological test, already available in most neurology departments, may offer a real-time readout of neurodegenerative processes that MRI can only capture after tissue has been lost. For a disease in which the earliest and most consequential damage often unfolds invisibly, a millisecond-scale signal from the eye may prove to be one of the most informative messages the brain ever sends.

Subject of Research: The association between visual evoked potential latency delays and MRI-based neurodegeneration measures in multiple sclerosis.

Article Title: VEP latency delays predicts MRI neurodegenerative outcomes in multiple sclerosis

Article References: Jakimovski, D., Weller, J., Zivadinov, R., Weinstock-Guttman, B., Golan, D., Zarif, M., Costello, F., Sergott, R. C., Galetta, S. L., Kenney, R., Balcer, L. J., Van Hecke, W., Smeets, D., Dhakal, B., Morrow, S. A., Covey, T. J., & Gudesblatt, M. (2026). VEP latency delays predicts MRI neurodegenerative outcomes in multiple sclerosis. Journal of Neurology, 273(10), Article 621. https://doi.org/10.1007/s00415-026-14151-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14151-y

Keywords: multiple sclerosis, visual evoked potentials, P100 latency, optical coherence tomography, retinal nerve fiber layer, brain volume, gray matter atrophy, T2-FLAIR lesion volume, neurodegeneration, MRI biomarkers, optic nerve, neurophysiology