The investigation began in the clinic. Within the prospective NOFF-S cohort, recruited through the Stroke Unit of the University Hospital Essen since October 2022, the researchers compared 26 patients who developed stroke-associated pneumonia with 326 who did not. Patients with pneumonia had more severe strokes at admission, measured by the National Institutes of Health Stroke Scale, and their 90-day outcome on the modified Rankin Scale was markedly worse. Pneumonia predicted poor outcome with a relative risk of 3.2 in both univariate and multivariable analyses, and the risk only modestly declined after adjustment for age, sex, and initial stroke severity. Flow cytometry of blood samples revealed something equally striking: patients who developed pneumonia showed a long-lasting deregulation of neutrophil subsets, with reduced proportions of CD15-low neutrophils persisting even three months after the stroke, hinting that the immune disturbance triggered by pneumonia was not a transient event.

To dissect mechanisms, the team turned to mice. They induced a transient 30-minute occlusion of the middle cerebral artery and, three days later, instilled Streptococcus pneumoniae directly into the trachea, replicating the typical timing of pneumonia onset in stroke patients. The results were dramatic. Pneumonia did not enlarge the initial infarct, but it significantly worsened neurological deficits, increased brain edema, and broke down the blood-brain barrier, as evidenced by increased IgG extravasation into the ischemic tissue. It also amplified the expression of the adhesion molecule ICAM-1 on cerebral microvessels, boosted infiltration of CD45-positive leukocytes, increased the density of platelet-rich microvascular thrombi marked by glycoprotein-Ib-alpha, and left behind extranuclear deposits of histone-H4 in the previously ischemic striatum, including in microglia and macrophages. A more severe 60-minute stroke model reproduced the same pattern, confirming that the findings were not an artifact of mild ischemia.

Perhaps the most sobering result concerned standard care. Amoxicillin, started three hours after infection and repeated every eight hours, reduced the bacterial load in the lungs and partially restored blood-brain barrier integrity and microvascular thrombosis. Yet it failed to improve neurological deficits, did not reduce the flood of neutrophils, monocytes, T cells, B cells, and NK cells invading the ischemic brain, and left extranuclear histone deposits untouched. This mirrors the disappointing record of prophylactic antibiotics in large randomized stroke trials such as STROKE-INF and PASS, which consistently failed to improve outcome despite reducing infection rates. Infection control, the study makes clear, is not the same as controlling the inflammatory fallout of infection.

Proteomic analysis of sorted blood neutrophils revealed why. Among 1,058 detected proteins, pneumonia shifted the neutrophil proteome toward a signature of degranulation, platelet activation, and NETosis, the explosive process by which neutrophils eject web-like structures of DNA studded with antimicrobial and tissue-damaging proteins. Twelve proteins were regulated in opposite directions by pneumonia and amoxicillin, including the chromatin-remodeling protein RUVBL1 and the histone H2B family member HIST2H2BB, interpreted as markers of ongoing NETosis and prior histone release. Notably, TOLLIP, a positive regulator of chronic inflammation known to exacerbate ischemic brain injury, rose with pneumonia and resisted amoxicillin, indicating a proinflammatory program that antibiotics alone cannot switch off.

With neutrophils implicated, the researchers tested a series of interventions. Depleting neutrophils with an anti-Ly6G antibody reversed the pneumonia-driven blood-brain barrier breakdown, brain edema, and microvascular thrombosis, establishing neutrophils as central mediators. But neutrophils are also essential for bacterial clearance, and post-stroke immunosuppression already compromises adaptive immunity, so depletion is not a clinically viable option. The team therefore targeted neutrophil products instead. Degrading existing neutrophil extracellular traps with DNase-I did nothing to help and actually increased hemorrhagic transformation of the infarcts, suggesting that NET DNA helps seal fragile ischemic vessels. Blocking NET formation with the gasdermin-D inhibitor LDC7559, or inhibiting the NET-bound enzyme myeloperoxidase with AZD4831, each reduced brain edema and microvascular thrombosis, but neither restored neurological function when given at the time of pneumonia.

Only one strategy delivered the complete package. A monoclonal antibody, BWA3, that neutralizes extracellular histone-H4 and H2A, administered just before and one day after pneumonia induction, reduced neurological deficits, shrank infarct volume, prevented blood-brain barrier breakdown, and curtailed microvascular thrombosis. Crucially, the benefits endured. Over 56 days of follow-up, histone-neutralized mice performed better on neurological scoring, tight rope walking, open field activity, and novel object recognition, and they developed significantly less brain atrophy. Histone blockade also increased the density of microglia and macrophages in the ischemic striatum while reducing their activation, without affecting microglial cell death, and it lowered circulating extracellular histone-H4 without altering NET levels, indicating that the antibody disarms histones rather than preventing their release.

The biology behind this protection fits a growing picture of extracellular histones as potent damage-associated molecular patterns. Once outside the cell, histones injure tissue by activating toll-like receptors and the complement cascade, triggering cytokine and chemokine release through MyD88, nuclear factor-kappa-B, and the NLRP3 inflammasome. In atherosclerosis models, externalized histone-H4 kills vascular smooth muscle cells, recruits more neutrophils, and perpetuates a cycle of NET release that destabilizes plaques, a cycle that histone neutralization can break. Extracellular histones have previously been identified as major mediators of death in sepsis, and administering histones to stroke mice worsens neurological deficits and infarct volume. What is new here is the demonstration that histones are the decisive link between a lung infection and progressive brain injury, and that intercepting them days after the stroke, at the moment pneumonia strikes, can still change the trajectory of recovery.

The clinical implications are tantalizing. Small-molecule inhibitors, inhibitory peptides, and neutralizing antibodies directed against histone-H4 are already in development for other inflammatory conditions, and the new data argue that stroke patients developing pneumonia could be a prime population for such therapies. The study also carries a caution for ongoing trials of intravenous DNase-I in ischemic stroke, three of which are currently registered, since delayed NET degradation increased brain hemorrhages in this model and should be monitored carefully. For now, the work redefines stroke-associated pneumonia not simply as an infection to be cured but as a neutrophil-driven storm whose toxic cargo, the histones, can be intercepted. If the mouse findings translate, the humble proteins that package DNA in every cell nucleus may become one of the most actionable drug targets in post-stroke care.

Subject of Research: Neutrophil-driven inflammatory brain injury and histone neutralization therapy in ischemic stroke complicated by bacterial pneumonia

Article Title: Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia

Article References: Yin, D., Li, A., Mohamud Yusuf, A., Shevchuk, O., Gronewold, J., Thiebes, S., Tertel, T., Wang, C., Hagemann, N., Zhang, Y., Graser, C., Tas, H., Fleischer, M., Kaltwasser, B., Frank, B., Tuz, A. A., Singh, V., Siemes, D., Pylaeva, E., … Hermann, D. M. (2026). Histone neutralization protects the ischemic brain against the consequences of stroke-associated pneumonia. Acta Neuropathologica, 152(1), Article 50. https://doi.org/10.1007/s00401-026-03097-0

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03097-0

Keywords: ischemic stroke, stroke-associated pneumonia, neutrophils, neutrophil extracellular traps, extracellular histones, histone neutralization, blood-brain barrier, microvascular thrombosis, Streptococcus pneumoniae, myeloperoxidase, brain atrophy, neurological recovery

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, refers to a spectrum of disorders affecting the brain’s tiniest blood vessels. Its fingerprints on magnetic resonance imaging are familiar to any neuroradiologist: bright patches of white matter hyperintensity, small cavities called lacunes, enlarged fluid-filled perivascular spaces, tiny cerebral microbleeds, and gradual shrinkage of brain tissue. Together, these markers underlie a substantial share of strokes and vascular cognitive impairment worldwide. Yet despite decades of study, the mechanisms that link failing small vessels to progressive brain injury remain incompletely understood, and few studies have examined how the brain’s waste-clearance systems, including the glymphatic pathway, contribute to the disease.

The choroid plexus sits at the heart of that question. This vascularized tissue, located in the lateral, third, and fourth ventricles of the brain, produces the bulk of cerebrospinal fluid and forms a critical barrier, the blood-cerebrospinal fluid barrier, that gates the passage of cells and molecules between the blood and the brain’s fluid compartments. The plexus is densely populated with immune cells and expresses a wide repertoire of inflammatory mediators, making it a key staging ground for neuroinflammation. Enlargement of the choroid plexus has previously been documented in neurodegenerative and neuroinflammatory conditions, including Alzheimer’s disease, and age-related changes in cerebrospinal fluid dynamics have been tied to structural remodeling of the tissue. Because small vessel disease and Alzheimer’s pathology so frequently coexist in elderly brains, the researchers reasoned that the choroid plexus might represent a previously overlooked biomarker in CSVD.

To test that idea, the team prospectively recruited 111 patients with cerebral small vessel disease and 69 healthy controls between 2016 and 2021 at two Chinese hospitals, with ethical approval and written informed consent. All participants underwent high-resolution brain MRI on a 3.0 Tesla scanner, including three-dimensional T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery, and susceptibility-weighted sequences. Two experienced neuroradiologists, blinded to clinical information, visually rated the conventional imaging markers of small vessel disease according to the STRIVE guidelines and combined them into a total CSVD score ranging from zero to six. Meanwhile, two trained physicians independently segmented the choroid plexus volume in each ventricle using ITK-SNAP software, normalizing the measurements to total intracranial volume. The segmentation agreement was excellent, with an intraclass correlation coefficient of 0.895.

The results were striking. Patients with small vessel disease showed significantly larger choroid plexus volumes in all three ventricular compartments compared with healthy controls. In the main cohort, the median lateral ventricle choroid plexus volume was 1.74 in patients versus 1.51 in controls, the third ventricle value was 0.34 versus 0.20, and the fourth ventricle value was 0.17 versus 0.12, with all differences highly significant even after adjusting for age and sex. Crucially, the enlargement tracked with disease severity. Larger plexus volumes correlated positively with white matter hyperintensity scores, lacunes, enlarged perivascular spaces in the basal ganglia, cerebral microbleeds, and the total CSVD score, and they also correlated with overall brain atrophy. The pattern points to a widespread process affecting the entire blood-cerebrospinal fluid barrier system rather than a localized abnormality confined to a single ventricle.

The study’s most novel contribution, however, came from a subgroup of 22 patients and 10 age- and sex-matched controls who underwent a specialized imaging technique rarely applied to this disease. The researchers infused ultrasmall superparamagnetic particles of iron oxide, known as USPIO, using the clinically approved iron supplement ferumoxytol at a dose of 3 milligrams per kilogram. These nanoparticles are engulfed by activated macrophages and microglia, the immune cells that congregate at sites of inflammation, so their accumulation reveals inflammatory activity in living tissue. Because the particles are cleared from plasma within roughly 24 to 48 hours, scanning 48 hours after infusion minimizes confounding from blood retention and perfusion effects, allowing the signal changes to primarily reflect iron uptake by activated myeloid cells. The technique has proven its worth in multiple sclerosis and stroke research, but its application to the choroid plexus in small vessel disease had remained largely unexplored.

Forty-eight hours after infusion, the patients’ choroid plexus lit up. Quantitative analysis of the change in signal intensity ratio, calculated relative to neck muscle tissue before and after injection, showed significantly greater USPIO uptake in the choroid plexus of all three ventricles in patients compared with controls. The inflammation was not confined to the plexus: patients also exhibited significantly increased uptake in the hippocampus, thalamus, and medulla oblongata, revealing a spreading inflammatory process that reaches deep gray matter structures essential for cognition. Moreover, the degree of choroid plexus inflammation correlated with conventional disease markers, with lateral ventricle plexus uptake correlating with white matter hyperintensity scores and fourth ventricle uptake correlating with both white matter hyperintensities and lacunes. Uptake in the putamen and thalamus also tracked with white matter damage, suggesting that plexus inflammation participates in the broader neuroinflammatory cascade accompanying small vessel injury.

Perhaps the most conceptually important finding was the direct link between structure and function. The volume of the lateral ventricle choroid plexus correlated positively with its own inflammatory signal, and even more strongly with the inflammatory signal of the fourth ventricle plexus, relationships that persisted after adjusting for age and sex. Inflammation in the lateral ventricle plexus was also strongly correlated with uptake in the hippocampus and thalamus, hinting at a blood-cerebrospinal fluid barrier mechanism that could connect small vessel disease to Alzheimer-type neurodegeneration. The authors propose a plausible biological sequence: chronic hypoperfusion or endothelial dysfunction in small vessel disease triggers an inflammatory response in the highly vascularized plexus, prompting immune cell infiltration and cellular hypertrophy that enlarge the tissue. The inflamed plexus, in turn, may release pro-inflammatory cytokines, alter cerebrospinal fluid composition, and disrupt the barrier, reducing the efficiency of glymphatic waste clearance and creating a vicious cycle of inflammation and brain injury.

The implications extend beyond mechanism. Choroid plexus volume could serve as a practical imaging biomarker that complements existing measures of small vessel disease burden, and USPIO-enhanced MRI offers a noninvasive way to monitor neuroinflammation and evaluate the efficacy of future anti-inflammatory treatments. Interventions aimed at the plexus-cerebrospinal fluid system might eventually emerge as therapeutic strategies. The researchers caution, however, that their study is cross-sectional and therefore cannot establish causation, that the USPIO subgroup was small and requires validation in larger cohorts, and that histological confirmation of the imaging signal is still lacking. They also note that the unweighted summation of imaging markers, while clinically practical, may obscure differences in pathological importance among individual features.

Even with those caveats, the work marks a significant step forward in reframing cerebral small vessel disease as a condition in which the brain’s immune interface plays a central role. If future longitudinal studies confirm that choroid plexus enlargement and inflammation precede the appearance of white matter damage and other conventional markers, the humble fluid-producing tissue tucked inside the ventricles could become an early warning system for one of the most common threats to the aging brain, opening a window for intervention long before strokes and dementia take their toll.

Subject of Research: Choroid plexus enlargement and neuroinflammation in cerebral small vessel disease measured with conventional and USPIO-enhanced MRI

Article Title: Choroid Plexus Enlargement and USPIO‐Based Inflammatory Feature in Cerebral Small Vessel Disease

Article References: Qu, Y., Ren, X., Fan, C., Li, C., Zhang, L., Zhang, Z., Li, S., Lai, Z., Cai, B., Fu, Y., Lin, Y., & Zhu, Z. (2026). Choroid Plexus Enlargement and USPIO ‐Based Inflammatory Feature in Cerebral Small Vessel Disease. Annals of Clinical and Translational Neurology, 13(10), 2078-2087. https://doi.org/10.1002/acn3.70382

Image Credits: AI Generated

DOI: 10.1002/acn3.70382

Keywords: cerebral small vessel disease, choroid plexus, USPIO, neuroinflammation, MRI, white matter hyperintensities, glymphatic system, blood-cerebrospinal fluid barrier, ferumoxytol, brain atrophy, microglia, cognitive decline

The study, published in Aging Cell, is among the first to benchmark eleven proteomic organ clocks against molecular, imaging, cognitive and physical biomarkers within a single population. The organ clocks were originally developed by mapping thousands of plasma proteins to their tissues of origin and training mathematical models to predict chronological age for organs including the brain, heart, liver, kidney, immune system and arteries. When the researchers applied these clocks to the Scottish cohort, they found substantial heterogeneity: organs within the same person appeared to age at strikingly different rates, and the organ age gaps were only mildly correlated with one another, with a mean pairwise correlation of 0.32. Extreme ageing, defined as an organ age gap exceeding two standard deviations from the population mean, most commonly affected just a single organ rather than several at once.

Despite this biological richness, the organ clocks delivered only modest prognostic power. Each standard deviation of accelerated organ ageing corresponded to a 16 to 43 percent higher mortality hazard over the follow-up period. The strongest effects emerged for the liver, with a hazard ratio of 1.43, followed by the immune system at 1.42 and the heart at 1.38. The proteomic brain age gap, at a hazard ratio of 1.31, performed almost identically to a brain age gap derived from magnetic resonance imaging, which scored 1.30. These findings replicate the original organ clock study, which reported a 17 to 53 percent mortality increase per standard deviation in a separate American cohort, confirming that the approach generalises across populations.

Yet several other biomarkers left the organ clocks behind. The clear champion was GrimAge2, a second-generation epigenetic clock that estimates biological age from DNA methylation patterns in blood. A single standard deviation of GrimAge2 acceleration conferred a 62 percent higher mortality hazard, the largest effect of any biomarker tested. Close behind came structural brain measures: smaller total brain volume raised mortality risk by 52 percent per standard deviation, and smaller grey matter volume by 44 percent. Reduced lung function also proved formidable, with a one-second forced expiratory volume deficit carrying a 51 percent higher hazard, and poorer general cognitive function adding 46 percent. All of these surpassed every proteomic organ clock in effect size.

The researchers then asked which biomarkers carried independent information when all were considered simultaneously. In a multivariable Cox model including 21 ageing measures among the 460 participants with complete data, only four survived: total brain volume, white matter hyperintensity volume, general cognitive function and walking time. GrimAge2, despite its stellar univariable performance, lost significance, not because it lacks biological relevance but because much of its prognostic signal overlaps with correlated measures. Together, the four independent biomarkers explained roughly 19 percent of the variance in mortality risk, while all 21 biomarkers combined raised that figure only to 23 percent, suggesting diminishing returns from adding further measures.

The variance decomposition was equally revealing. Chronological age and sex accounted for just 2 percent of mortality risk, with lifestyle factors adding 4 percent. GrimAge2 contributed a further 6 percent, proteomic organ clocks 8 percent and physical function measures 9 percent. Brain-related measures, combining neuroimaging and cognition, accounted for around 16 percent, roughly double any other single domain. For the authors, this underscores that brain health, encompassing atrophy, cerebrovascular damage and cognitive capacity, is a particularly powerful window on survival in old age, likely because the brain regulates essential physiological functions and because atrophy captures neurodegenerative processes long before clinical diagnosis.

Beyond benchmarking clocks, the team mined the full plasma proteome for mortality signals. Using the SomaScan 11K platform, which quantifies nearly 10,000 protein targets from a small plasma sample, they identified 368 proteins significantly associated with all-cause mortality after adjustment for age and sex. The strongest positive associations belonged to GDF15, a stress- and inflammation-induced cytokine, with a hazard ratio of 1.56, followed by WFDC2 at 1.47 and TIMP1 at 1.45. Notably, GDF15 ranked as the second strongest mortality predictor overall, behind only GrimAge2, and three of the nine proteins whose DNA methylation surrogates are built into GrimAge2 appeared among the top twenty. On the protective side, higher circulating levels of neuropeptide S, BAGE3 and ABCC6 each corresponded to roughly 41 to 42 percent lower mortality risk per standard deviation.

Gene set enrichment analysis revealed a striking functional dichotomy among these proteins. Those whose higher levels predicted death were overwhelmingly enriched for immune processes, including antimicrobial humoral immune responses, chemokine and cytokine activity, and interleukin-4 and interleukin-13 signalling, painting a picture of inflammaging and immunosenescence, the chronic low-grade inflammation and immune decline that characterise ageing. Proteins associated with survival, by contrast, were enriched for genomic integrity: nucleosome assembly, regulation of the G2/M cell cycle transition, damaged DNA binding and ribosome biogenesis. Among the protective candidates were Sirtuin-2 and Caspase-2, both involved in DNA damage response and tumour suppression, with higher levels linked to 18 and 32 percent lower mortality risk respectively. An elastic net penalised regression across all 9,703 protein targets distilled the signal to just 37 proteins, with GDF15 carrying the largest positive coefficient and strong concordance with the univariate results.

The study has limitations the authors acknowledge. The cohort consists of relatively healthy, ethnically homogeneous Scots born in 1936, so validation in more diverse populations is needed. The analyses relied on single baseline measurements rather than longitudinal trajectories, examined all-cause rather than cause-specific mortality, and depended on one proteomics platform. The findings are observational and cannot establish causality. Still, the practical implications are considerable: simple, inexpensive measures such as walking speed, lung function and cognition rival or exceed costly molecular assays, while integrative biomarkers trained directly on mortality outcomes, like GrimAge2, currently offer the strongest single-molecule performance. Whether organ clocks add value for cause-specific mortality, such as distinguishing cardiac from neurological deaths, remains an open question.

What emerges is a clear message for the booming biological-ageing industry: no single number captures how fast someone is ageing. Organs age at their own pace, blood proteins tell one story, brain scans another, and the most informative forecast comes from combining complementary measures across modalities. As the world’s population over 60 doubles to a projected 2.1 billion by 2050, choosing the right combination of biomarkers could determine who benefits from early intervention, and the new results suggest that protecting the brain, preserving lung capacity and taming chronic inflammation may matter more than any single molecular clock.

Subject of Research: Multimodal ageing biomarkers and plasma proteomic signatures associated with all-cause mortality in older adults

Article Title: Multimodal Ageing Biomarkers and Plasma Proteomic Signatures Associated With All‐Cause Mortality

Article References: Pyrgioti, M., Eguiagaray, I. M., Redmond, P., Corley, J., Bastin, M. E., Hernández, M. V., Russ, T. C., Wardlaw, J. M., Hannon, E., Deary, I. J., Walker, K. A., Tucker‐Drob, E. M., Cox, S. R., Marioni, R. E., & Harris, S. E. (2026). Multimodal Ageing Biomarkers and Plasma Proteomic Signatures Associated With All‐Cause Mortality. Aging Cell, 25(10), Article e70747. https://doi.org/10.1111/acel.70747

Image Credits: AI Generated

DOI: 10.1111/acel.70747

Keywords: biological age, proteomic organ clocks, epigenetic clock, GrimAge2, all-cause mortality, plasma proteomics, GDF15, brain atrophy, cognitive function, lung function, immunosenescence, Lothian Birth Cohort 1936

The research team, led by Rozemarijn Mattiesing of Amsterdam University Medical Center together with colleagues in Siena and London, revisited data from the REFLEX and REFLEXION trials, a pair of linked phase 3 studies that followed people experiencing their first demyelinating attack, known as a clinically isolated syndrome, for five years. From the combined dataset, the team analyzed 262 participants who had begun treatment with subcutaneous interferon beta-1a early in the disease course. The cohort was typical of very early multiple sclerosis: nearly 62 percent were women, the average age was just under 32, and the median disability score on the Expanded Disability Status Scale was a modest 1.5. Over the five-year follow-up, roughly 40 percent of participants converted to clinically definite multiple sclerosis, while about 18 percent showed confirmed worsening on the disability scale.

The technical centerpiece of the study was the way the blood measurements were handled. Serum samples collected at baseline and at months 6, 12, and 24 were analyzed using the ultrasensitive single molecule array technology, run on a Simoa HD-1 instrument, which can detect the vanishingly small concentrations of neurofilament light chain that circulate in blood. Rather than reporting raw concentrations, the researchers converted each value into an age- and body mass index-adjusted z-score, anchored to a large reference database of healthy controls. This normalization matters because neurofilament levels rise steadily with age and vary with body composition, so a raw value can be misleading without context. The z-score approach allowed the team to ask whether a given patient’s levels were high or low relative to what would be expected for a healthy person of the same age and build.

The first major finding concerned the shape of the protein’s curve over time. Neurofilament levels were highest at baseline, which was expected given that participants had all experienced recent inflammatory attacks, and then fell sharply during the first year of treatment before stabilizing during the second year at levels approaching those of healthy controls. The decline was steepest in patients who had shown acute inflammation on their baseline scans, marked by gadolinium-enhancing lesions, and in those carrying a heavier burden of T2 lesions. Patients with at least one enhancing lesion at baseline had significantly higher z-scores at baseline, month 6, and month 12 than those without, a gap that narrowed as treatment suppressed the inflammatory storm. This pattern suggests that the falling blood signal tracks the resolution of inflammatory disease activity under therapy.

Cross-sectionally, the baseline blood values told a coherent story about disease activity. Higher baseline z-scores correlated with larger T2 lesion volumes, and the relationship held both in patients with enhancing lesions and in those without, hinting that axons inside pre-existing lesions continue to degenerate even when acute contrast enhancement is absent. The baseline values also correlated with the volume of lesions that subsequently shrank during the first year, a relationship the researchers attribute to the resolution of inflammatory edema rather than true tissue repair. In a subgroup of 70 patients, they directly quantified this by measuring how much of the baseline gadolinium-enhancing lesion volume dissolved into shrinking lesions over the first year, and found a strong correlation with baseline neurofilament levels. Intriguingly, the roughly 23 percent of patients classified as showing pseudoatrophy, an apparent brain volume loss driven by fluid shifts rather than true tissue loss, had significantly higher baseline values than those who did not.

When the team turned to prediction, the picture became more complicated. Higher baseline z-scores were significantly associated with a higher risk of converting to clinically definite multiple sclerosis over five years, with an odds ratio of 1.18, and with a faster time to conversion, with a hazard ratio of 1.16. Baseline levels also correlated with faster central atrophy, measured as ventricular enlargement, during the final three years of the study. But in regression models that simultaneously included baseline MRI variables, namely normalized brain volume, T2 lesion volume, and gadolinium-enhancing lesion volume, alongside age, sex, and baseline disability, the blood biomarker lost its statistical significance for every one of these outcomes. In other words, the scan already contained the prognostic information that the blood test was offering.

The longitudinal analyses, however, revealed something the MRI could not supply on its own. Changes in the z-score during the second year of the study, once treatment had stabilized, were linked to new and enlarging lesions in the same period, and, crucially, predicted faster global and central atrophy during the last three years of follow-up even after correcting for baseline MRI measures, demographics, and the baseline blood value. A rising neurofilament signal during the stable treatment phase, the authors conclude, marks a shift toward a more neurodegenerative disease profile that precedes measurable brain tissue loss. Notably, blood changes during the first year behaved differently: after accounting for baseline values, increases during year one tracked new and enlarging lesions, reflecting breakthrough inflammatory activity, while decreases accompanied the shrinking of lesions as edema resolved.

The authors are careful to frame these findings within the study’s limitations. The cohort consisted entirely of very early, relapsing-onset patients treated with a platform therapy, so the results cannot be generalized to progressive disease or to the modern high-efficacy treatments that are now standard of care. The measures of resolving edema and pseudoatrophy were exploratory, spinal cord lesions and relapse data were unavailable, and the conclusions apply at the group level rather than to individual patients. The absence of any relationship between blood values and confirmed disability progression likely reflects the low disability levels and small number of progressors in this young cohort. Replication in larger, more heterogeneous populations, ideally with cerebrospinal fluid measurements and additional biomarkers, remains necessary before the test can enter routine clinical practice.

Even so, the study lands at a consequential moment for the field. Blood-based neurofilament testing is cheap, minimally invasive, and easily repeated, making it an attractive complement or alternative to MRI, which is expensive, burdensome, and imperfect at capturing the degenerative component of the disease. The new results suggest a division of labor: a single baseline measurement is essentially a proxy for the inflammatory activity an MRI already documents, and is therefore most useful where MRI is unavailable, while serial measurements during stable treatment may flag patients drifting toward neurodegeneration before their scans show it. For a disease in which treatment decisions increasingly hinge on detecting subclinical progression early, the finding that a rising blood signal predicts future brain volume loss independent of MRI could ultimately reshape how neurologists monitor therapy, even as the scans retain their crown as the strongest single predictor at diagnosis.

Subject of Research: The predictive value of serum neurofilament light chain for disease progression in early multiple sclerosis

Article Title: The predictive value of serum neurofilament light chain levels beyond MRI measures for clinical and radiological disease progression in the earliest stages of multiple sclerosis

Article References: Mattiesing, R. M., Gentile, G., Battaglini, M., De Stefano, N., Brouwer, I., Strijbis, E. M. M., Uitdehaag, B. M. J., Barkhof, F., Vrenken, H., & Schoonheim, M. M. (2026). The predictive value of serum neurofilament light chain levels beyond MRI measures for clinical and radiological disease progression in the earliest stages of multiple sclerosis. Journal of Neurology, 273(10), Article 584. https://doi.org/10.1007/s00415-026-14100-9

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14100-9

Keywords: multiple sclerosis, neurofilament light chain, biomarker, MRI, brain atrophy, clinically isolated syndrome, disease progression, interferon beta-1a, REFLEX trial, lesion activity, neurodegeneration, prognosis