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NCT Number: NCT07824297

NAIF 2.0 - COGNIFY

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.

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Key information

Conditions

Dural Arteriovenous Fistula Cardiovascular Abnormalities Cardiovascular Diseases Central Nervous System Vascular Malformations Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Glymphatic System Nervous System Diseases Nervous System Malformations Vascular Malformations

Age range

18 year–99 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Università di Bologna, Bologna, Italy

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Brain MRI

Diagnostic Test

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.

Primary outcomes

  1. Mean DTI-ALPS Index at Baseline and 6 Months After Endovascular Embolization

    Time frame: 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.

  2. Mean MK at Baseline and 6 Months After Endovascular Embolization

    Time frame: 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.

  3. Mean FW at Baseline and 6 Months After Endovascular Embolization

    Time frame: 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 outcomes

  1. Spearman Rank Correlation Between Cognard Grade and Baseline DTI-ALPS Index

    Time frame: 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.

  2. Spearman Rank Correlation Between Cognard Grade and Baseline MK

    Time frame: 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.

  3. Spearman Rank Correlation Between Cognard Grade and Baseline FW

    Time frame: 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.

Other outcomes

  1. Mean DTI-ALPS Index According to Prespecified Clinical and Angiographic Characteristic

    Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.

    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.

  2. Mean MK According to Prespecified Clinical and Angiographic Characteristics

    Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.

    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.

  3. Mean FW According to Prespecified Clinical and Angiographic Characteristics

    Time frame: Baseline/pre-treatment MRI and follow-up MRI approximately 6 months after endovascular embolization.

    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.

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Sponsors and collaborators

Lead sponsor

Hospital Universitari Vall d'Hebron Research Institute

Other

Collaborators

  • Oxford University Hospitals NHS Trust
  • University of Bologna
  • University of Oxford

Registry information

Official study title

NAIF 2.0 - COGNIFY: Cognitive Impairment in Patients With Intracranial Dural Arteriovenous Fistulae: Exploration & Understanding

Acronym: NAIF 2

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Sep 17, 2026
Registry last updated
Sep 17, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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