The classical definition of moyamoya disease rests on two features: progressive stenosis and occlusion of the terminal portion of the internal carotid artery, where it enters the circle of Willis, and the appearance of abnormal basal collateral networks that resemble a puff of smoke on angiography, the meaning of the Japanese word moyamoya. When the same angiographic pattern occurs in patients with identifiable associated conditions, such as neurofibromatosis or prior radiation therapy, it is traditionally labeled moyamoya syndrome. Ota contends that this dichotomy, while clinically convenient, does not correspond to consistent differences in vascular pathology. Radiological patterns and disease progression are often indistinguishable between the two groups, and unilateral or secondary cases can evolve into bilateral phenotypes identical to idiopathic disease.

The historical analysis at the heart of the review is revealing. Before the term moyamoya was coined by Suzuki and Takaku in 1969, Japanese investigators described these patients under a broader anatomical heading, and early national consensus documents were titled Guidelines for the Diagnosis of Occlusive Disease of the Circle of Willis. In that original framing, steno-occlusive disease of the circle of Willis was a descriptive category encompassing heterogeneous non-atherosclerotic intracranial arteriopathies, without assuming a single underlying mechanism. Over time, the striking and reproducible moyamoya phenotype absorbed the broader concept, particularly in East Asian clinical practice, until the two became implicitly equated. Western classification systems took a different path, generally interpreting moyamoya-like collateral networks as nonspecific responses to chronic arterial occlusion. The result has been a phenotype-centered framework in Japan and an etiology-centered approach in Western practice, with little common ground between them.

To restore that common ground, the review proposes an operational definition of steno-occlusive disease of the circle of Willis with explicit anatomical boundaries: progressive steno-occlusive disease involving the supraclinoid or terminal internal carotid artery, the proximal anterior cerebral artery, the proximal middle cerebral artery, and the origin of the posterior communicating artery, while excluding isolated distal branch disease and primary basilar atherosclerosis. Within this territory, moyamoya vasculopathy is repositioned as the predominant but non-exclusive angiographic phenotype. The review also describes early or precollateral stages, in which focal stenosis of the terminal carotid artery occurs without established moyamoya vessels, and non-moyamoya or mixed patterns, in which circle-of-Wilis-centered stenosis fails to fulfill classical criteria. These categories describe vascular phenotypes rather than etiologic disease entities, and they may evolve or overlap over time.

A key insight of the framework is the temporal dissociation between arterial narrowing and collateral formation. The basal collaterals that give moyamoya its name have long been treated as disease-defining, but the review argues they are better understood as adaptive vascular responses to chronic arterial narrowing, appearing only after hemodynamic compensation becomes necessary. Early-stage cases presenting with isolated stenosis are difficult to classify under phenotype-based criteria, yet within the location-defined framework they can be interpreted as early disease, supporting serial imaging and longitudinal assessment over rigid categorical labeling. This perspective may reduce diagnostic uncertainty at initial presentation, when the angiographic picture is incomplete.

Genetic evidence provides some of the strongest support for this reconceptualization. Genome-wide association studies identified RNF213, particularly the p.R4810K variant, as the major susceptibility factor for moyamoya disease, with the association most pronounced in Japanese and Korean patients and less frequent in Chinese patients. The marked geographic distribution of p.R4810K supports a founder effect rather than a universally shared moyamoya-associated variant. In European-ancestry patients, p.R4810K is extremely rare or absent, yet sequencing studies have identified multiple heterogeneous rare RNF213 variants, including p.D4013N, p.R4062Q, and p.A4399T, that preferentially cluster within the C-terminal region encompassing the RING-finger domain, although the pathogenic significance of individual variants remains incompletely established. No single RNF213 variant, in other words, accounts for the shared vascular phenotype across populations.

Even more consequential is the question of penetrance. Many heterozygous carriers of RNF213 variants remain asymptomatic throughout life, indicating that the gene alone is insufficient to determine disease expression. Conversely, increasing genetic burden appears to influence severity: homozygous individuals tend to present with earlier onset, more severe steno-occlusive changes, broader vascular involvement, more rapid progression, posterior circulation involvement, and increased frequency of extracranial manifestations such as pulmonary artery stenosis. Recent evidence also suggests additional modifiers, with the HAPLN3 p.T34A variant proposed as a factor associated with increased penetrance among carriers of p.R4810K, supported by whole-exome sequencing and endothelial-cell experiments, though these findings remain preliminary. RNF213 variants have also been linked to non-moyamoya arteriopathies, including intracranial atherosclerotic disease and large-artery ischemic stroke, further undermining the idea of a disease-defining gene.

Functionally, RNF213 encodes a protein with ATPase and ubiquitin ligase activity implicated in angiogenesis, endothelial function, and vascular remodeling, with emerging roles in immune and inflammatory pathways including interferon signaling and host defense. This supports a model in which RNF213 acts as a context-dependent modifier that amplifies vascular vulnerability under inflammatory or environmental stress. But genetic factors alone cannot explain the most puzzling feature of the condition: its remarkably consistent localization to the terminal internal carotid artery and circle of Willis across diverse clinical contexts. To address this, the review turns to developmental biology, noting that mural cells such as vascular smooth muscle cells and pericytes arise from heterogeneous embryological origins, with cephalic neural crest cells contributing to the forebrain vasculature in a regionally restricted manner. The concept of vascular cephalic neurocristopathy has been proposed as a possible explanation for the preferential involvement of the terminal carotid region, although the review is careful to note that direct lineage mapping of human cerebral arteries remains limited and the hypothesis remains unproven.

The resulting multi-hit model integrates three dimensions: developmental and anatomical features that define the disease-prone territory, genetic factors such as RNF213 that influence susceptibility and phenotypic expression, and environmental or inflammatory processes that act as triggers of onset and progression. This formulation separates lesion localization from genetic determinants and offers a coherent explanation for anatomical specificity, phenotypic variability, and incomplete penetrance, though it remains hypothetical and requires validation through integrated genetic, developmental, and longitudinal studies. Clinically, the framework does not alter established treatment strategies at present. Surgical revascularization remains the principal treatment for symptomatic disease with impaired cerebral perfusion, and decisions should continue to rest on clinical presentation, progression, and objective hemodynamic evidence rather than on the new label. The potential value lies instead in the precollateral stage: stenosis centered on the circle of Willis without established moyamoya vessels should not automatically be dismissed as unrelated or nonspecific, and longitudinal imaging with hemodynamic assessment may help identify progression toward a classical phenotype, justifying closer surveillance without extending surgical indications beyond current evidence.

The review acknowledges its own limitations candidly. The proposed anatomical boundaries remain partially arbitrary, overlap with other intracranial arteriopathies may occur, and genetic associations are influenced by population structure and phenotypic heterogeneity. No biomarker is currently specific enough for diagnosis, and emerging candidates such as circulating inflammatory mediators, endothelial markers, microRNAs, and angiogenic factors remain clinically unestablished. No disease-modifying therapy or gene therapy targeting RNF213 variants is available, although patient-derived induced pluripotent stem cell and gene-editing platforms offer preclinical routes toward therapeutic targets. The framework is presented as an iterative model rather than a fixed taxonomy, one whose value lies in providing an anatomical basis for integrating emerging genetic, imaging, and biological insights. If future prospective studies confirm that the proposed phenotypes represent biologically meaningful subgroups, the field may move toward classification systems built not on a single angiographic pattern or a single gene, but on the shared territory where the disease begins.

Subject of Research: Reconceptualizing moyamoya vasculopathy within steno-occlusive disease of the circle of Willis

Article Title: Reframing moyamoya vasculopathy within steno-occlusive disease of the circle of Willis

Article References: Ota, T. (2026). Reframing moyamoya vasculopathy within steno-occlusive disease of the circle of Willis. Frontiers in Stroke, 5, Article 1890618. https://doi.org/10.3389/fstro.2026.1890618

Image Credits: AI Generated

DOI: 10.3389/fstro.2026.1890618

Keywords: moyamoya disease, circle of Willis, RNF213, stroke, intracranial arteriopathy, genetic susceptibility, neural crest, cerebral revascularization, vascular remodeling, moyamoya syndrome, steno-occlusive disease, neurovascular imaging

The study, led by Yuhui Sha and Jun Ni, together with collaborators including Joanna M. Wardlaw of the University of Edinburgh, set out to systematically characterize symptomatic diffusion-weighted imaging lesions, known as sDWI lesions, and incidental DWI lesions, known as iDWI lesions, in patients with probable CAA. Diffusion-weighted imaging is an MRI sequence exquisitely sensitive to acute cellular injury: when blood flow to brain tissue fails and cells begin to swell with cytotoxic edema, water molecules lose their freedom to diffuse, and the affected region lights up brightly on the scan. In CAA, these bright spots have been the subject of a running debate. Autopsy work from previous groups, including studies by Ter Telgte and colleagues, has suggested that DWI-positive lesions in CAA correspond histologically to microinfarcts, confirming that they represent genuine ischemia rather than hemorrhage or artifact. Yet the clinical relevance, prevalence, and mechanisms of these lesions remained contested.

To resolve the question, the team drew on a prospective cohort of cerebral small vessel disease patients recruited at Peking Union Medical College Hospital between March 2017 and February 2026. Using the Boston criteria version 1.5, the standard clinicoradiological framework for diagnosing CAA without tissue biopsy, they enrolled 185 patients with probable CAA. Each participant underwent detailed baseline clinical assessment and multimodal MRI, including imaging markers of small vessel disease such as lacunes, cerebral microbleeds, and cortical superficial siderosis, the latter being a sign of chronic blood leaking over the surface of the brain. Ninety-nine of the patients returned for follow-up MRI, generating 163 scans in total, which allowed the researchers to estimate not only cross-sectional prevalence but also cumulative incidence over time.

The results were revealing in two directions. First, ischemia turned out to be anything but rare. Symptomatic DWI lesions were detected in 29 patients, while incidental DWI lesions, discovered on scans performed for other reasons, appeared in 49 patients, more than a quarter of the entire cohort. Kaplan–Meier analysis of the followed subgroup showed that over three years, the cumulative incidence of new symptomatic DWI lesions was 9.45 percent, with a 95 percent confidence interval of 0.67 to 17.46 percent, while the cumulative incidence of incidental lesions was considerably higher at 25.74 percent, with a confidence interval spanning 15.2 to 34.97 percent. In other words, roughly one in four CAA patients followed longitudinally was destined to develop a small ischemic lesion within three years, most of them without any clinical fanfare.

Second, and perhaps more striking, the two lesion types behaved like two different diseases. When the researchers constructed lesion probability maps to visualize topography, symptomatic DWI lesions clustered predominantly in deep brain regions, accounting for 72.7 percent of their locations. Incidental lesions, by contrast, were mainly found in cortical and juxtacortical regions, the ribbon of gray matter and the immediately underlying white matter, in 62.5 percent of cases. This anatomical split is not trivial. Deep and superficial cerebral territories are supplied by different vascular trees, with deep perforating arterioles and leptomeningeal cortical vessels subject to different hemodynamic stresses and pathological processes. A preferential distribution suggests a preferential mechanism.

That suspicion was confirmed by prospective Cox regression analysis, which adjusted for age and sex and, for the incidental lesions, also for traditional vascular risk factors and focal superficial siderosis. For symptomatic DWI lesions, the independent predictors were the number of traditional vascular risk factors, including hypertension, diabetes mellitus, coronary artery disease, and smoking, with a hazard ratio of 2.968 per additional risk factor, and the presence of lacunes, small old infarcts typical of hypertensive arteriopathy, with a hazard ratio of 1.187. Both reached conventional statistical significance, with P values of 0.013 and 0.016 respectively. This profile points toward the familiar machinery of atherosclerotic and hypertensive small vessel disease, superimposed on the amyloid-laden vasculature of CAA patients.

Incidental DWI lesions told a different story. Their independent predictors were lacunes, with a hazard ratio of 1.158, disseminated cortical superficial siderosis, with a hazard ratio of 2.994, and lobar cerebral microbleed grade, with a hazard ratio of 2.059. Notably, traditional vascular risk factors did not independently predict these silent lesions once adjustments were made. Disseminated siderosis and a heavy burden of lobar microbleeds are both hallmarks of advanced amyloid pathology, marking vessels that leak blood products into the subarachnoid space and brain parenchyma. Their association with cortical and juxtacortical ischemic lesions fits a mechanistic picture in which amyloid-laden leptomeningeal and cortical vessels, damaged by both amyloid deposition and hemosiderin-related injury, suffer episodic failure of perfusion, producing tiny cortical microinfarcts that the patient never notices.

The implications ripple outward in several directions. Clinically, the findings suggest that when a CAA patient presents with an acute neurological event, a DWI-positive lesion in deep structures is likely to be associated with conventional vascular risk factors and may warrant aggressive management of those factors. Conversely, incidental cortical lesions in a patient with disseminated siderosis may signal active amyloid-related vascular injury, which has been linked in prior work to increased risks of both future hemorrhage and cognitive decline. Earlier studies have shown that silent ischemic infarcts are associated with hemorrhage burden in CAA, and that DWI lesions after intracerebral hemorrhage predict recurrent stroke, so the new prospective risk factor data give clinicians a sharper tool for risk stratification.

Scientifically, the study reframes DWI-positive lesions as a dynamic window on small vessel disease activity. Traditional imaging markers such as microbleeds and siderosis are cumulative, recording injury that may have accumulated over years. DWI lesions, by contrast, are acute, appearing and resolving within days to weeks, and their signal characteristics evolve in a characteristic sequence as microinfarcts mature. Their detection rate in a longitudinal cohort therefore reflects ongoing disease activity, in the same way that incident troponin release reflects active myocardial injury. The authors propose that DWI-positive lesions could serve as a useful imaging marker of SVD activity and injury in future longitudinal studies and clinical trials of CAA. This matters because the CAA therapeutic pipeline is, for the first time, showing real signs of life. Immunotherapy trials with anti-amyloid antibodies such as ponezumab have been conducted, and a Phase 2 study of the RNA interference therapeutic ALN-APP, designed to reduce production of amyloid precursor protein, is currently recruiting patients with CAA. Trials like these need sensitive, quantifiable markers of target engagement and disease progression, and DWI lesion rates could fill that role.

There are, as always, caveats. The cohort of 185 patients, and the 99 with follow-up imaging, is modest by the standards of national registry studies, and the confidence interval around the three-year incidence of symptomatic lesions is wide, reflecting the relative rarity of these events. Probable CAA by Boston criteria is not histologically confirmed disease, although the criteria perform well in autopsy-validated settings. The observational design cannot definitively separate correlation from causation: lacunes may predict DWI lesions because they share upstream causes rather than because old infarcts directly provoke new ones. And MRI at typical clinical field strengths can miss very small cortical microinfarcts, meaning the true incidence of ischemia in CAA may be even higher than these figures suggest. Nevertheless, the consistency of the topographical and risk factor dissociation across analyses lends credibility to the central conclusion.

The broader message is a conceptual one. CAA, the study concludes, is not simply a hemorrhagic disease with an occasional ischemic afterthought. Cerebral ischemia is common, mechanistically patterned, and readable on standard clinical MRI. Symptomatic deep lesions track the burden of systemic vascular risk, while silent cortical lesions track the severity of amyloid vasculopathy itself, a dissociation that echoes recent work in CAA and CADASIL cohorts showing high prevalences of incidental DWI lesions with distinct clinical associations. For a disease whose diagnosis has historically hinged on documenting bleeding, the growing recognition that acute ischemic lesions can be counted, mapped, and followed over time offers both a warning and an opportunity: the amyloid-diseased vessel fails in more ways than one, and each failure mode now has its own signature that clinicians and trialists can learn to read.

Takayasu arteritis, often called “pulseless disease,” primarily affects the aorta and its major branches. Inflammation can thicken the arterial wall, reduce the diameter of the vessel, and eventually restrict blood flow to the brain, arms, kidneys, or other organs. Neurological complications may include transient ischemic attacks, strokes, dizziness, visual disturbances, and fainting. Because symptoms and laboratory markers do not always reflect the full extent of vascular injury, clinicians increasingly rely on imaging to identify active inflammation and structural narrowing. The new work explores an unusual imaging target: the amygdala, a small almond-shaped structure located in the medial temporal lobe and involved in emotional processing, stress responses, autonomic regulation, and communication with the immune system.

The investigators analyzed data from 303 people with Takayasu arteritis who underwent whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography, commonly known as ¹⁸F-FDG PET/CT. The radioactive glucose analogue is taken up by metabolically active cells, allowing PET to visualize tissues with increased glucose consumption. In large-vessel vasculitis, inflammatory cells in the arterial wall can accumulate FDG and produce a measurable signal. The researchers also quantified FDG uptake in the amygdala and bone marrow, as well as in affected vessel walls, while collecting clinical information, blood-test results, and vascular imaging findings. Participants were followed for a median of 27 months, during which cerebrovascular and other adverse events were recorded.

The principal result was not uniform across the entire cohort. When all participants were analyzed together, amygdalar standardized uptake values, or SUVs, were not significantly associated with cerebrovascular events. SUV is a semi-quantitative measure that estimates how much tracer has accumulated in a region after accounting for factors such as injected dose and body size. SUVmax represents the highest measured activity within a region of interest, whereas SUVmean reflects the average activity. This distinction matters because a single intense voxel can influence SUVmax, while SUVmean may provide a broader estimate of regional metabolic activity. In the overall study population, neither measurement consistently separated patients who experienced cerebrovascular events from those who remained event-free.

A clearer pattern emerged in the treatment-naïve subgroup. Patients who had suffered cerebrovascular events showed lower amygdalar activity than those without such events. Mean amygdalar SUVmax was 9.3 compared with 10.3 in event-free patients, while mean SUVmean was 6.6 compared with 7.4. The differences were statistically significant, with p values of 0.011 and 0.003, respectively. When the researchers divided patients according to amygdalar metabolic activity, 24.3 percent of people in the low-SUV group had experienced cerebrovascular events, compared with 15.9 percent in the higher-SUV group. The low-activity group also had higher immunoglobulin G and immunoglobulin A levels and lower lymphocyte counts, suggesting that reduced amygdalar uptake may coexist with distinctive systemic immune features.

The relationship became especially notable when the researchers examined structural disease in the arteries supplying the head and neck. Higher amygdalar SUVmax was identified as an independent protective factor against combined carotid and vertebral artery stenosis. The reported odds ratio was 0.876, with a p value of 0.032. An odds ratio below one indicates that, within the statistical model, increasing amygdalar activity was associated with lower odds of the outcome after accounting for other evaluated factors. The carotid arteries deliver blood to much of the brain’s anterior circulation, while the vertebral arteries contribute to the posterior circulation. Narrowing in both systems can substantially reduce cerebral blood flow and increase the risk of ischemic injury.

Follow-up findings provided additional support for the signal, although they also illustrated the complexity of the biology. Patients who later experienced cerebrovascular events had a significantly lower amygdalar SUVmax than a group described as having new-onset symptoms without the same event outcome: 8.2 compared with 10.4. This observation raises the possibility that amygdalar metabolic activity could reflect a brain-body state associated with vascular vulnerability before or during clinically important disease. However, PET uptake is not a direct measurement of stress, emotion, or immune control. It can be influenced by age, medication, glucose levels, scanner characteristics, image-processing methods, brain structure, and other medical conditions. The amygdala is also small, making accurate measurement vulnerable to partial-volume effects, in which limited spatial resolution causes activity from neighboring tissues to blend into the region of interest.

The authors’ interpretation builds on a growing body of research concerning the brain’s role in cardiovascular and immune regulation. Earlier studies in other populations have linked resting amygdalar activity with cardiovascular events, while experimental work has shown that stress-related neural circuits can influence the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, bone marrow activity, and inflammatory signaling. The amygdala communicates with regions that regulate autonomic output and endocrine responses, and these pathways can affect circulating immune cells and the behavior of inflammatory tissues. In Takayasu arteritis, such neuroimmune interactions could theoretically alter the inflammatory environment surrounding the aorta and its branches. The present study does not prove this mechanism, but it adds a new imaging-based association to the emerging concept that vascular inflammation may be shaped by both immune processes and neural activity.

The findings should therefore be viewed as a potential biomarker discovery rather than a clinical test ready for routine use. The study was observational, and its results cannot establish whether reduced amygdalar activity contributes to arterial stenosis, results from chronic vascular disease, or reflects another factor shared by patients with worse outcomes. The absence of a significant association in the full cohort also suggests that treatment exposure and disease history may modify the relationship. In addition, the reported associations came from a single clinical cohort and require confirmation in independent populations using standardized PET acquisition and analysis. Future studies could combine serial brain PET, vascular imaging, inflammatory biomarkers, autonomic measurements, psychological assessments, and long-term clinical follow-up. If the association is reproduced, amygdalar metabolism might eventually help identify patients who need closer neurological surveillance, more detailed carotid and vertebral imaging, or intensified prevention strategies.

For now, the study offers a striking shift in perspective on Takayasu arteritis. The disease is traditionally assessed through arterial anatomy, blood-flow measurements, laboratory inflammation markers, and metabolic activity within the vessel wall. The new results suggest that the brain itself may contain information about the risk of vascular complications. A low amygdalar PET signal cannot yet predict an individual stroke, and it should not replace established clinical evaluation. Nevertheless, the work highlights how a scan originally used to map glucose metabolism can reveal connections between emotional-neural circuitry, systemic immunity, and arterial injury. As researchers continue to decode these pathways, the amygdala may become an important part of the story of how large-vessel inflammation affects the whole body.

Subject of Research: Takayasu arteritis, amygdalar metabolism, cerebrovascular events, and carotid-vertebral artery stenosis

Article Title: Amygdalar metabolic activity associated with cerebrovascular events and carotid-vertebral artery stenosis in takayasu arteritis

Article References: Ma L, Wu B, Wu S, et al. “Amygdalar metabolic activity associated with cerebrovascular events and carotid-vertebral artery stenosis in takayasu arteritis.” European Journal of Nuclear Medicine and Molecular Imaging (2026). References include Tawakol A, Ishai A, Takx RA, et al. “Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.” The Lancet. 2017;389:834–845.

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08090-z

Keywords: Takayasu arteritis; amygdala; ¹⁸F-FDG PET/CT; cerebrovascular events; carotid artery stenosis; vertebral artery stenosis; neuroimmune interaction; vascular inflammation; brain metabolism; nuclear medicine imaging