An observational study in Dural Arteriovenous Fistula and Glymphatic System, sponsored by Hospital Universitari Vall d'Hebron Research Institute. Recruiting at 3 sites in 3 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2026-09-17.
Sponsored by Hospital Universitari Vall d'Hebron Research Institute · Observational
The goal of this observational study is to learn whether intracranial dural arteriovenous fistulae, abnormal connections between arteries and veins in the covering of the brain, may affect a brain's waste-clearance system, known as the glymphatic system.
The main question it aims to answer is: "Does glymphatic system function change after routine endovascular embolization of an intracranial dural arteriovenous fistula?" Participants who are already scheduled to receive endovascular embolization as part of their regular medical care will undergo advanced brain MRI before treatment and again about 6 months after treatment. Researchers will compare the MRI findings before and after embolization to explore whether treatment is associated with changes in glymphatic-related brain imaging markers.
Intracranial dural arteriovenous fistulae (dAVF) are acquired vascular malformations characterized by an abnormal connection between dural arteries and cortical veins or dural sinuses, characterized by altered venous drainage. Treatment decision has traditionally been driven by risk of rupture and brain haemorrhage, although recent findings from the NAIF study showed that patients with dAVF may also present with cognitive impairment that can improve after successful endovascular embolization (Gramegna et al., 2023). However, the mechanisms underlying this potentially reversible cognitive dysfunction remain poorly understood.
Abnormal venous pressure and flow may disrupt brain homeostasis and interfere with the glymphatic system, a clearance pathway closely linked to perivascular spaces and meningeal lymphatic vessels, whose function is determined by a correct pressure gradient between arteries and veins. Glymphatic dysfunction has been associated with cognitive impairment in neurodegenerative and cerebrovascular disorders and its alterations appear to be reversible following pharmacological or surgical interventions.
NAIF 2 hypothesizes that altered venous drainage in dAVF causes glymphatic dysfunction that may improve after endovascular treatment. Our study protocol is centred around an advanced multishell diffusion-weighted MRI which will be used to assess in vivo and non-invasively this hypothesis. From diffusion-weighted images, metrics related to glymphatic system function will be computed, mainly DTI-ALPS (Taoka et al., 2017), together with diffusion kurtosis imaging-derived mean kurtosis (DKI-MK) and free-water (FW) imaging, which may provide complementary information on microstructural and interstitial fluid alterations (Sacchi et al., 2024).
This prospective multicentre observational study will recruit patients with angiographically confirmed unruptured dAVF undergoing embolization at Vall d'Hebron University Hospital and Oxford University Hospitals, with methodological support from the University of Bologna. Two MRI session are planned: one at baseline and one approximately 6 moths after treatment. Advanced MRI-derived glymphatic metrics will be compared before and after embolization, with changes in DTI-ALPS, DKI-MK, and FW measures as the primary endpoint. Demonstrating reversible glymphatic dysfunction could provide a biological explanation for cognitive impairment related to dAVF and its recovery after embolization and help to reconsider how a treatment decision is taken, especially in low-grade fistulae, considering other factors beyond haemorrhagic risk alone.
Hospital Universitari Vall d'Hebron Research Institute is the lead sponsor of 276 studies on the registry; 64 are open to participants now.
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Patients with angiographically confirmed diagnosis of unruputred intracranial dAVFs, aged 18-99 years, candidate for endovascular embolization treatment with curative intent.
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Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients with angiografically confirmed diagnosis of intracranial dAVF, aged 18-99 years, candidate for endovascular will be invited to participate in this study
Diagnostic Test: Brain MRI
Participants will undergo a brain MRI on a 3T scanner at baseline assessment and approximately 6 months after endovascular embolization. The MRI protocol includes routinary morphologic sequences (e.g., 3D T1-weighted imaging, T2-weighted FLAIR, susceptibility-weighted imaging), as well as a multi-shell diffusion MRI with multiple b-values and gradient directions. These sequences will be used to assess conventional brain findings and diffusion-derived metrics potentially related to glymphatic function, including DTI-ALPS, DKI-MK and FW imaging. The main otcome of the study is to evaluate changes in these metrics in relation to treatment.
Mean DTI-ALPS Index at Baseline and 6 Months After Endovascular Embolization
The diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) index will be calculated from directional diffusivities measured in prespecified projection- and association-fiber regions of interest (ROIs). The regional measurements will be combined according to the prespecified DTI-ALPS calculation to obtain one DTI-ALPS index per participant at each time point. DTI-ALPS values will be summarized as the mean and standard deviation at baseline and follow-up. Baseline and follow-up values will be compared within participants using a two-sided paired-samples t-test. A Wilcoxon signed-rank test will be performed as a sensitivity analysis if marked departures from normality or influential outliers are identified. Lower DTI-ALPS values indicate greater lower diffusivity along the perivascular-space direction, suggestive of a glymphatic system impairment. The DTI-ALPS index is unitless.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Mean MK at Baseline and 6 Months After Endovascular Embolization
Mean Kurtosis (MK) will be derived from multi-shell diffusion MRI. Voxelwise mean kurtosis values within white matter ROIs covering the whole brain will be calculated and summarized as the mean and standard deviation at baseline and follow-up. Baseline and follow-up values will be compared within participants using a two-sided paired-samples t-test. A Wilcoxon signed-rank test will be performed as a sensitivity analysis if marked departures from normality or influential outliers are identified. Higher mean kurtosis values indicate a greater degree of non-Gaussian water diffusion, suggestive of a glymphatic system impairment. MK is unitless.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Mean FW at Baseline and 6 Months After Endovascular Embolization
Free-water (FW) will be estimated from multi-shell diffusion MRI using a free-water imaging model. Voxelwise FW values within white matter ROIs covering the whole brain will be calculated and summarized as the mean and standard deviation at baseline and follow-up. Baseline and follow-up values will be compared within participants using a two-sided paired-samples t-test. A Wilcoxon signed-rank test will be performed as a sensitivity analysis if marked departures from normality or influential outliers are identified. FW is a unitless volume fraction ranging from 0 to 1, with higher values indicating a greater proportion of extracellular free water, suggestive of a glymphatic system impairment.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Spearman Rank Correlation Between Cognard Grade and Baseline DTI-ALPS Index
dAVF severity will be assessed by digital subtraction angiography using the Cognard classification and treated as an ordinal variable. The DTI-ALPS index will be derived from diffusion MRI and expressed as a unitless index. The association between Cognard grade and baseline DTI-ALPS index will be assessed using Spearman's rank correlation coefficient. Results will be reported as Spearman's rho with a 95% confidence interval.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Spearman Rank Correlation Between Cognard Grade and Baseline MK
dAVF severity will be assessed by digital subtraction angiography using the Cognard classification and treated as an ordinal variable. MK will be derived from multi-shell diffusion kurtosis imaging and expressed as a unitless value. The association between Cognard grade and baseline mean kurtosis will be assessed using Spearman's rank correlation coefficient. Results will be reported as Spearman's rho with a 95% confidence interval.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization
Spearman Rank Correlation Between Cognard Grade and Baseline FW
dAVF severity will be assessed by digital subtraction angiography using the Cognard classification and treated as an ordinal variable. FW will be derived from multi-shell diffusion MRI and expressed as a unitless fraction ranging from 0 to 1. The association between Cognard grade and baseline free-water fraction will be assessed using Spearman's rank correlation coefficient. Results will be reported as Spearman's rho with a 95% confidence interval.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Mean DTI-ALPS Index According to Prespecified Clinical and Angiographic Characteristic
The DTI-ALPS index will be derived from diffusion MRI and expressed as a unitless index. DTI-ALPS values will be summarized separately according to prespecified clinical and angiographic characteristics, including clinical presentation, dAVF location and angiographic treatment response. Each characteristic will be evaluated separately. Analyses will be considered exploratory and will be performed only when the number of participants in the relevant categories is sufficient.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Mean MK According to Prespecified Clinical and Angiographic Characteristics
MK will be derived from multi-shell diffusion kurtosis imaging and expressed as a unitless value. MK values will be summarized separately according to prespecified clinical and angiographic characteristics, including clinical presentation, dAVF location and angiographic treatment response. Each characteristic will be evaluated separately. Analyses will be considered exploratory and will be performed only when the number of participants in the relevant categories is sufficient.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
Mean FW According to Prespecified Clinical and Angiographic Characteristics
FW will be derived from multi-shell diffusion MRI and expressed as a unitless fraction ranging from 0 to 1. FW will be summarized separately according to prespecified clinical and angiographic characteristics, including clinical presentation, dAVF location and angiographic treatment response. Each characteristic will be evaluated separately. Analyses will be considered exploratory and will be performed only when the number of participants in the relevant categories is sufficient.
Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.
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