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 research team, led by Leandro Castañeyra-Ruiz and colleagues at CHOC Children’s Research Institute, integrated three lines of evidence: quantitative magnetic resonance imaging in a cohort of forty-two preterm and term infants, multiplex profiling of inflammatory proteins in cerebrospinal fluid, and laboratory experiments using primary human choroid plexus cells. Their central hypothesis was that inflammatory cerebrospinal fluid, rich in growth factors such as vascular endothelial growth factor and epidermal growth factor, could reactivate proliferative programs that are normally active only during fetal development, causing the choroid plexus to enlarge in infants who go on to develop hydrocephalus.

The imaging findings were striking in their consistency. On T2-weighted MRI scans, choroid plexus thickness increased in a stepwise fashion across clinical categories. In the axial plane, mean thickness measured 3.44 millimeters in control infants, 4.53 millimeters in preterm infants with intraventricular hemorrhage managed without surgery, and 5.39 millimeters in infants who ultimately required cerebrospinal fluid diversion. Sagittal measurements showed an even more pronounced gradient, rising from 3.51 millimeters in controls to 6.19 millimeters in the diversion group. Statistical analysis revealed that clinical category alone explained roughly 38 to 41 percent of the variance in thickness, and the differences between the most severely affected infants and controls were highly significant in both imaging planes.

Critically, the researchers went beyond simple group comparisons. Because infants requiring diversion were also the most premature at birth, with a mean gestational age of just over 27 weeks compared with nearly 38 weeks in controls, the team used multivariable regression to adjust for gestational age at birth and postmenstrual age at imaging. The association between clinical progression and choroid plexus thickness survived these adjustments, indicating that the enlargement was not simply a byproduct of earlier birth or a different maturational stage at the time of scanning. The team also controlled for ventricular size using the frontal and occipital horn ratio, a standard measure of ventricular dilation, and for hemorrhage severity grade. Even after full adjustment, clinical category remained independently associated with thickness, while ventricular size itself showed no independent relationship with axial thickness. In other words, the choroid plexus appeared to be enlarging as part of the disease process itself, not merely being stretched by expanding ventricles.

To probe the cellular basis of this remodeling, the researchers turned to laboratory experiments with primary human choroid plexus epithelial cells and endothelial cells, the two principal cell types of the tissue. They exposed the cells for seventy-two hours to different cerebrospinal fluid conditions: an artificial fluid control, a low-inflammatory fluid obtained from patients with spinal muscular atrophy, and a growth factor-enriched inflammatory fluid derived from patients with severe traumatic brain injury. Multiplex cytokine analysis confirmed that the inflammatory fluid carried significantly elevated concentrations of vascular endothelial growth factor, and that hemorrhage-derived and injury-derived inflammatory fluids shared this growth factor signature.

The proliferative response was substantial. In epithelial cells, the proportion of nuclei staining positive for proliferating cell nuclear antigen, a marker of active DNA synthesis, rose from 23.7 percent under artificial fluid conditions to 42.1 percent under inflammatory exposure. In endothelial cells the shift was even larger, climbing from 44.26 percent to 77.22 percent. When the researchers supplemented the culture media with recombinant epidermal growth factor, epithelial proliferation surged to 60 percent in artificial fluid and 71.7 percent in low-inflammatory fluid, while recombinant vascular endothelial growth factor likewise boosted endothelial proliferation. These results demonstrated that growth factors alone are sufficient to drive robust proliferation in these immature tissue cells.

The team then tested whether the response depended on specific growth factor receptors. Blocking the epidermal growth factor receptor with erlotinib numerically reduced epithelial proliferation back toward baseline, though the reduction did not reach statistical significance, so the authors were careful to note that epidermal growth factor receptor dependence was not formally established. In contrast, pharmacological inhibition of the vascular endothelial growth factor receptor significantly reduced endothelial proliferation, cutting it by nearly 40 percentage points relative to inflammatory fluid alone and restoring it toward control levels. Taken together, the pharmacological evidence was stronger for vascular endothelial growth factor pathway involvement than for the epidermal growth factor arm, but both experiments supported the general principle that inflammatory fluid acts through growth factor signaling.

Independent published datasets lent further biological plausibility to the model. Reanalysis of a publicly available RNA sequencing dataset from a neonatal rat hemorrhage model revealed a 12.7-fold elevation of Mki67, a marker of actively cycling cells, in choroid plexus tissue from hemorrhaged animals compared with controls. Separate work has shown that hemoglobin, the primary injury mediator in intraventricular hemorrhage, directly induces choroid plexus epithelial proliferation at concentrations 37 to 65 percent above control levels. Clinical proteomic studies have also documented a temporal arc: inflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha are elevated during the acute phase of post-hemorrhagic hydrocephalus and decline with treatment, while transthyretin, a constitutive secretory protein of the choroid plexus, is sharply suppressed during the acute phase and recovers as treatment progresses. This pattern is consistent with a two-stage process in which acute inflammatory injury triggers proliferative activation and altered epithelial identity, followed by persistence of a structurally remodeled tissue state.

The developmental timing of these events may be the key to why prematurity matters so much. During late gestation, roughly 24 to 28 weeks of human development, the epithelial and endothelial compartments of the choroid plexus remain structurally immature and retain proliferative competence. The tissue expresses receptors for insulin-like growth factor 1, epidermal growth factor, and vascular endothelial growth factor, and it responds to these signals. In a full-term infant, these growth programs have largely quieted. But in a baby born at the edge of viability, an inflammatory surge from hemorrhage or infection may find a tissue still poised to grow, effectively prolonging developmental programs that should have been time-limited and producing structural expansion that persists beyond the acute inflammatory phase.

The authors are careful about what their findings do and do not show. Cerebrospinal fluid secretion rates and transporter activity were not directly measured, so choroid plexus enlargement on MRI should not be read as evidence of fluid overproduction, and hydrocephalus remains a multifactorial disease involving impaired fluid resorption, scarring, and pathway obstruction. The in vitro experiments used injury-derived inflammatory fluid as a model of growth factor-enriched exposure rather than hemorrhage-specific neonatal fluid, and the cross-sectional imaging design cannot establish whether enlargement persists over time. Still, if the findings are validated prospectively, choroid plexus thickness could become an adjunct imaging biomarker for identifying which infants with hemorrhage are most likely to progress to shunt dependency, and modulation of growth factor pathways within defined developmental windows could emerge as a testable therapeutic strategy for a condition that currently offers clinicians few options beyond surgery.

Subject of Research: Inflammatory cerebrospinal fluid exposure and choroid plexus remodeling in preterm acquired hydrocephalus

Article Title: Choroid plexus remodeling associated with inflammatory CSF exposure in preterm acquired hydrocephalus

Article References: Jison, G., Ramos, N., Cotrim-Gomes, F., Lee, S., Hanak, B. W., Muhonen, M., & Castañeyra-Ruiz, L. (2026). Choroid plexus remodeling associated with inflammatory CSF exposure in preterm acquired hydrocephalus. iScience, 29(10), Article 117759. https://doi.org/10.1016/j.isci.2026.117759

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117759

Keywords: hydrocephalus, choroid plexus, preterm infants, intraventricular hemorrhage, cerebrospinal fluid, inflammation, VEGF, EGF, MRI, proliferation, neonatology, iScience

The Innovative Project Award provides $200,000 over two years and is deliberately designed to back high-risk, high-reward science. Eligible projects spanned the full breadth of biomedical inquiry, from basic laboratory studies of cells and molecules to clinical investigations and population health research, and applicants could propose work across the entire human lifespan, from children and adolescents through middle age and late life. The prioritization of innovation over incremental safety reflects a conscious strategy by both societies: rather than extending established research programs, they wanted to seed ideas that conventional funding mechanisms might consider too speculative, but that could open entirely new avenues for preventing stroke and heart disease in people living with chronic headache disorders.

This year’s co-funded award goes to Juliana Navia Pelaez, Ph.D., an assistant professor at St. Louis University School of Medicine in St. Louis, Missouri, for a project titled “Neurogenic Priming of Perivascular Macrophages by Migraine-Associated Peptides Increases Stroke Risk.” Her work targets a question that has long puzzled clinicians: why some people who suffer from migraine face a higher risk of stroke. Researchers have traditionally concentrated on the blood vessels themselves, since during a migraine attack these vessels may tighten, swell, or alter the way blood moves through them. But attention is now shifting toward another, less obvious player — the brain’s own resident immune cells, which stand guard along the vessels and help protect neural tissue from injury.

Pelaez’s central hypothesis is that repeated migraine attacks may push these vascular immune cells into a state of chronic overactivation. “If migraines happen over and over, these immune cells might stay ‘on’ for too long. When this happens, they might accidentally make the blood vessels weaker,” Pelaez said. “If the vessels get weaker, the brain might have a harder time protecting itself from a stroke.” In practical terms, the project will map which signals released during a migraine activate these brain immune cells, and then compare how the cells respond to a subsequent stroke in animals that have experienced migraine-like events versus those that have not. The comparison is designed to isolate the specific contribution of migraine biology to stroke vulnerability, rather than attributing everything to shared risk factors such as hypertension or smoking.

The translational implications could be considerable. “If our idea is right,” Pelaez added, “this could help scientists find new ways to prevent strokes in people with chronic migraine, maybe by calming these overactive brain cells or blocking the signals that bother them.” Such a strategy would represent a fundamentally different approach to stroke prevention in this population. Instead of managing vascular risk factors after the fact, clinicians might one day intervene directly on the neuroimmune signaling cascade that links repeated migraine attacks to cumulative vessel damage — a possibility that could reshape how neurologists and cardiologists jointly manage patients with frequent or chronic migraine.

The Heart Association’s three additional awards extend the same investigative ambition across distinct mechanistic frontiers. The first goes to Andrea M. Harriott, M.D., Ph.D., an assistant professor in neurology at Massachusetts General Hospital in Boston, for a study titled “The Impact Of Cortical Spreading Depolarizations On Endothelial Phenotype, Neovascularization, and Collateral Remodeling.” Migraine with aura has long been epidemiologically linked to stroke and heart attack, and earlier thinking held that this association might simply reflect an elevated burden of conventional risk factors among people with aura. Harriott’s project will test a more direct possibility: that the long-term exposure to the mechanisms underlying migraine aura — cortical spreading depolarizations, waves of altered electrical and metabolic activity that sweep across the brain — causes lasting structural and functional harm to cerebral blood vessels. Her team will examine protein-level changes in the cells lining vessel walls, the formation of new blood vessels, and the remodeling of collateral circulation that the brain relies on when its primary supply routes are compromised.

The second award supports Matthew T. Bender, M.D., an associate professor at the University of Rochester in Rochester, New York, whose project, “Defining The Glymphatic-Hemodynamic Axis In IIH: A Novel Multi-Scale Quantitative MRI Framework,” addresses idiopathic intracranial hypertension, or IIH. This headache disorder disproportionately affects overweight women of childbearing age, and clinicians believe it arises from elevated pressure inside the skull driven by excess cerebrospinal fluid. Recent evidence, however, suggests the disorder may also involve dysfunction of the brain’s waste clearance network, known as the glymphatic system. Bender’s team will develop a new magnetic resonance imaging framework capable of visualizing both the glymphatic system and cerebral blood flow without contrast dye or invasive procedures. By scanning IIH patients before and after venous stenting — a procedure that opens narrowed veins draining the brain — the researchers hope to determine how restoring venous outflow affects waste clearance and hemodynamics, potentially establishing imaging markers that could guide treatment decisions.

The third award funds Neil Dani, Ph.D., an assistant professor at Vanderbilt University in Nashville, Tennessee, for “Illuminating Nociceptive And Analgesic Mechanisms Of Choroid Plexus In Migraine And Obesity Models.” Dani’s work responds to the rising prevalence of obesity-related migraine, a clinically important overlap given that both conditions share inflammatory signaling pathways. His focus is the choroid plexus, a small structure inside the brain’s ventricles that produces cerebrospinal fluid and acts as a highly regulated interface, or gate, between the body and the central nervous system. The working hypothesis is that inflammatory signals generated in the body during obesity may travel through the cerebrospinal fluid via the choroid plexus, sensitizing pain circuits and increasing migraine frequency or severity. The project will characterize inflammation patterns in this structure, identify cellular rewiring and immune signaling changes associated with obesity and migraine, and test whether clinically approved drugs — including acetazolamide, a long-standing medication already used in related contexts — can reduce both swelling and pain signaling in experimental models.

Taken together, the four projects sketch a research landscape in which headache disorders and vascular medicine are no longer treated as separate silos. Each award interrogates a different node of the heart-brain axis: immune cells that patrol cerebral vessels, the electrical storms of migraine aura and their vascular aftermath, the interplay of intracranial pressure and brain waste clearance, and the inflammatory crosstalk between metabolism, body-wide immune signaling, and pain. The funders emphasize that these efforts demonstrate the shared commitment of the American Headache Society and the American Heart Association to advancing brain health research, and the co-funding structure itself may prove as influential as the science it supports, encouraging cross-disciplinary training, shared patient cohorts, and unified endpoints across neurology and cardiology.

The initiative also sits within a far larger funding tradition. Supporting scientific research and discovery through programs of this kind is a cornerstone of the century-old American Heart Association’s lifesaving mission. Since 1949, the Association has invested more than $6.3 billion in cardiovascular, cerebrovascular, and brain health research, making it the single largest non-profit, non-governmental supporter of heart and brain health research in the United States. Officials note that knowledge generated through this funding continues to save lives and directly affect millions of people across the country and around the world. For the millions who live with migraine and other headache disorders — and for the clinicians who care for them — the new awards offer something more immediate than long-term promise: a concrete, funded research agenda that treats the pounding in the head and the health of the heart and brain’s vessels as inseparable parts of the same biological story.

Subject of Research: Funded research projects investigating the links between migraine, headache disorders, and cardiovascular and cerebrovascular health

Article Title: New scientific research projects study heart/brain connection to migraines, headaches

Article References: New scientific research projects study heart/brain connection to migraines, headaches. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: migraine, stroke, American Heart Association, American Headache Society, cerebrovascular health, cortical spreading depolarization, idiopathic intracranial hypertension, glymphatic system, choroid plexus, perivascular macrophages, obesity-related migraine, research funding