Dural Arteriovenous Fistula, Glymphatic System
Conditions
Keywords
MRI, DTI, Glymphatic System, Dural Arteriovenous Fistula
Brief summary
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.
Detailed description
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.
Interventions
DIAGNOSTIC_TESTBrain 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.
Sponsors
Hospital Universitari Vall d'Hebron Research Institute
University of Bologna
University of Oxford
Oxford University Hospitals NHS Trust
Study design
Observational model
OTHER
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Participant is willing and able to give informed consent for participation in the study. * Male or Female, aged 18 to 99 years. * Angiographically confirmed diagnosis of unruptured intracranial dAVF. * Candidate for endovascular embolization treatment with curative intent. * Able to undergo Brain MRI.
Exclusion criteria
* Contraindication to angiographic embolization procedures. * Acute intracranial haemorrhage secondary to dAVFs rupture and/or venous hypertension. * Any significant disease or disorder which, in the opinion of the investigator, might influence the participant's ability to participate in the study, other contraindications to MRI such as certain metallic implants.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean DTI-ALPS Index at Baseline and 6 Months After Endovascular Embolization | Baseline/pre-treatment MRI and follow-up MRI approximately 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. |
| Mean MK at Baseline and 6 Months After Endovascular Embolization | Baseline/pre-treatment MRI and follow-up MRI approximately 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. |
| Mean FW at Baseline and 6 Months After Endovascular Embolization | Baseline/pre-treatment MRI and follow-up MRI approximately 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spearman Rank Correlation Between Cognard Grade and Baseline DTI-ALPS Index | Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization. | 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. |
| Spearman Rank Correlation Between Cognard Grade and Baseline MK | Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization | 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. |
| Spearman Rank Correlation Between Cognard Grade and Baseline FW | Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization. | 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. |
Countries
Italy, Spain, United Kingdom
Contacts
CONTACTLaura Ludovica Gramegna, MD, PhD
Outcome results
None listed