Highlights
Dual Risk Association
Patients with high burdens of basal ganglia enlarged perivascular spaces (BGPVS ≥21) face a significantly elevated risk of both ischemic stroke and major bleeding when receiving antithrombotic therapy.
Biomarker Potential
BGPVS acts as a robust imaging biomarker for cerebral small vessel disease (SVD), offering predictive value independent of traditional markers like cerebral microbleeds or white matter hyperintensities.
Personalized Risk Stratification
Incorporating BGPVS assessment into clinical practice may refine the risk-benefit analysis for initiating or continuing oral anticoagulants or antiplatelet agents in elderly populations.
Background and Clinical Significance
Perivascular spaces (PVSs), also known as Virchow-Robin spaces, are fluid-filled compartments surrounding small blood vessels as they penetrate the brain parenchyma. While small PVSs are a normal feature of brain anatomy, their enlargement (ePVS) is increasingly recognized as a hallmark of cerebral small vessel disease (SVD) and glymphatic system dysfunction. In the clinical setting, the presence of BGPVS has been linked to hypertension and deep-seated SVD pathology, yet its role in predicting future vascular events—particularly in the context of antithrombotic use—has remained poorly defined.
As the global population ages, the number of patients requiring long-term antithrombotic therapy for the prevention of ischemic stroke or cardiovascular events is rising. However, these therapies carry the inherent risk of major bleeding and intracranial hemorrhage (ICH). Identifying patients at high risk for both ischemic and hemorrhagic complications is a major challenge in geriatric neurology. The BAT2 study sought to address this gap by evaluating whether the severity of BGPVS could serve as a reliable predictor of adverse outcomes in a large, real-world cohort of patients.
The BAT2 Study: Methods and Population
This prospective, multicenter observational study (the BAT2 study) enrolled 5,065 patients across 52 hospitals in Japan between 2016 and 2019. The cohort consisted of individuals with established cerebrovascular or cardiovascular diseases who were either starting or continuing oral antithrombotic therapy (antiplatelets, anticoagulants, or both).
Baseline Assessment and Imaging
All participants underwent multimodal MRI at baseline. Centralized evaluators assessed several markers of SVD, including:
– White matter hyperintensities (WMH)
– Cerebral microbleeds (CMBs)
– Lacunes
– Basal ganglia enlarged perivascular spaces (BGPVS)
BGPVS burden was quantified on a single axial slice at the level of the basal ganglia and categorized into four grades: 0, 1-10, 11-20, or ≥21. This rigorous imaging protocol ensured that the predictive value of BGPVS was adjusted for the presence of other established SVD markers.
Outcomes and Statistical Analysis
The primary outcomes included major bleeding, intracranial hemorrhage (ICH), ischemic stroke, other ischemic events, and all-cause mortality. The median follow-up period was 2.0 years. Multivariable Cox proportional hazards models were utilized to determine adjusted hazard ratios (aHR), controlling for age, sex, vascular risk factors (hypertension, diabetes, etc.), and other SVD imaging features.
Key Findings: The Dual Risk Profile of BGPVS
The study population had a median age of 74 years, with a baseline distribution of antithrombotic use consisting of 75.4% on antiplatelets and 29.7% on anticoagulants. The BGPVS distribution showed that 14.0% of the cohort had a high burden (≥21).
Significant Association with Ischemic Stroke
High BGPVS burden was strongly associated with a higher incidence of ischemic stroke. Patients with a BGPVS count of ≥21 had an adjusted hazard ratio (aHR) of 2.58 (95% CI 1.21-5.50) compared to those with no BGPVS. When treated as an ordinal variable, each per-unit increase in BGPVS category was associated with a 28% increase in ischemic stroke risk (aHR 1.28; 95% CI 1.07-1.53).
Elevated Risk of Major Bleeding
Crucially, the study found that BGPVS severity also predicted major bleeding events. Patients in the highest BGPVS category (≥21) faced a fourfold increase in the risk of major bleeding (aHR 4.04; 95% CI 1.17-13.92). The risk per-unit increase was also significant (aHR 1.38; 95% CI 1.07-1.77). Interestingly, while the trend suggested an increased risk for intracranial hemorrhage (ICH), the association did not reach statistical significance, possibly due to the relatively low number of ICH events (n=54) during the follow-up period.
Mortality and Other Ischemic Events
No significant associations were found between BGPVS burden and overall mortality or non-stroke ischemic events. This suggests that the impact of BGPVS is specifically localized to the cerebrovascular and systemic hemorrhagic risks rather than general systemic decline.
Expert Commentary: Mechanistic Insights and Clinical Utility
Biological Plausibility
The association between BGPVS and ischemic stroke is likely mediated by the role of PVSs in the glymphatic system. Enlargement of these spaces suggests impaired waste clearance and fluid transport within the brain, which may exacerbate neuroinflammation and endothelial dysfunction. In the basal ganglia, ePVSs are specifically linked to hypertensive arteriopathy. This underlying vasculopathy likely contributes to both the occlusion of small penetrating arteries (leading to ischemic stroke) and the fragility of vessels (predisposing to bleeding).
Clinical Implications
For clinicians, these findings suggest that MRI reports should move beyond simply noting ‘age-related changes.’ Quantifying BGPVS provides actionable data. In a patient with a BGPVS count ≥21, the decision to use potent antithrombotics must be weighed against a significantly higher risk of major bleeding. While the study does not suggest withholding necessary therapy, it advocates for more aggressive management of modifiable risk factors—such as blood pressure—and closer monitoring in these high-risk individuals.
Comparison with Other SVD Markers
Traditionally, cerebral microbleeds (CMBs) have been the primary focus for bleeding risk assessment. However, the BAT2 data demonstrates that BGPVS provides independent prognostic information. This suggests that BGPVS may reflect a different aspect of small vessel vulnerability, perhaps related to interstitial fluid drainage rather than just focal microhemorrhage.
Strengths and Limitations
Strengths
– Large, prospective, multicenter design involving 5,065 patients.
– Centralized imaging evaluation, reducing inter-rater variability.
– Comprehensive adjustment for concurrent SVD markers (WMH, lacunes, CMBs).
– Real-world clinical setting including both antiplatelet and anticoagulant users.
Limitations
– The study was conducted in a Japanese population; thus, the generalizability to other ethnic groups with different SVD phenotypes (e.g., higher prevalence of cerebral amyloid angiopathy in Caucasians) requires further investigation.
– The follow-up period of 2.0 years is relatively short for assessing long-term mortality and rare events like ICH.
– While BGPVS was identified as a risk factor, the study did not explore the impact of specific antithrombotic dosages or types (e.g., DOACs vs. Warfarin) on the BGPVS-related risk.
Conclusion and Summary
The BAT2 study provides compelling evidence that a high burden of basal ganglia enlarged perivascular spaces is a significant predictor of both ischemic stroke and major bleeding in patients receiving antithrombotic therapy. As an easily identifiable marker on standard clinical MRI, BGPVS should be integrated into the vascular risk assessment of elderly patients. Future research should focus on whether specific therapeutic interventions, such as intensive blood pressure control, can mitigate the risks associated with high BGPVS burdens.
Funding and Clinical Trials
This study was supported by the Japan Agency for Medical Research and Development (AMED). The BAT2 study is registered at ClinicalTrials.gov (NCT02660190) and the University Hospital Medical Information Network (UMIN-CTR 000020259).
References
1. Iwamoto S, Miwa K, Koga M, et al. Impact of Basal Ganglia Perivascular Spaces on Ischemic and Hemorrhagic Risks in Patients Taking Antithrombotic Therapies. Neurology. 2026;106(7):e214745. PMID: 41861278.
2. Wardlaw JM, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822-838.
3. Doubal FN, et al. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease, not luminal atheroma. Stroke. 2010;41(3):450-454.