Blood-brain Barrier Quantification in Cerebral Small Vessel Disease

Blood-Brain Barrier Permeability Quantification in Cerebral Small Vessel Disease -- Reproducibility of Dynamic Contrast-enhanced MRI

Cerebral small vessel disease (cSVD) encompasses all pathological processes that affect the small vessels of the brain. On brain-MRI cSVD is characterized by structural brain abnormalities such as white matter lesions (WMLs). Clinically, cSVD is related to acute syndromes as lacunar stroke but also to more chronic health problems such as cognitive decline. Recent literature suggests that a disrupted blood brain barrier (BBB), leading to elevated BBB permeability, may play a pivotal role in the aetiology of cSVD and lacunar stroke. The BBB is a complex system of neuronal, glial and vascular cells which main function is to shield the brain from toxic components and regulate the homeostasis. Elucidating the role of the BBB may have far reaching consequences for the treatment of cSVD patients and the reduction of recurrence rate of the disease. This could lead to a better quality of life among cSVD patients and reduce the economic burden on society. Currently the exact contribution and extent of a possibly defective BBB in cSVD remains largely unclear, due to the lack of a reliable method to accurately quantify the BBB permeability in cSVD patients. As a result, the current treatment consists of treating the cardiovascular risk factors, often with poor results.

Quantification of the BBB permeability provides an objective measure of the integrity of the BBB and as such aids the study of the role of the BBB. The aim of this study is to realize a clinically applicable MRI-method to quantify the BBB permeability. Moreover, the method can be used to study the involvement of BBB disruption in other neuropathologies including Alzheimer's disease, vascular dementia, hypertension and diabetes.

Primary Study Objective:

To realize a clinically applicable quantification of BBB permeability using DCE-MRI by determining the reproducibility of the DCE-MRI method

Secondary Study Objective:

To achieve the shortest scan duration without compromising the reliability of the BBB permeability quantification.

Hypotheses:

1. Using an optimized DCE-MRI method to quantify the BBB permeability, the BBB permeability can be reliably determined in cSVD patients.
2. The scan duration can be shortened without compromising the reliability of the BBB permeability quantification.

Study Overview

• Status: Completed
• Conditions: Cerebral Hemorrhage; Cerebral Small Vessel Disease; Blood-Brain Barrier Permeability; Cortical Stroke
• Intervention / Treatment: Procedure: Dynamic contrast enhanced Brain MRI

• Study Type: Observational
• Enrollment (Actual): 17

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 5800
      • Maastricht University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

General:

• Age >18 years old
• The condition of the patient must be well enough to allow participation in the study, which is decided in consultation with the treating physician.

cSVD patients: - patients who present with a transient ischemic attack (TIA) and cSVD related abnormalities on brain MRI. MRI abnormalities include extended white matter lesions, (asymptomatic) lacunar infarcts, microbleeds and enlarged Virchow-Robin spaces. The patients are eligible when the first DCE-MRI scan can be performed 8-12 weeks after the TIA to avoid the acute phase, and the second MRI-scan within four weeks after the first.

Cortical stroke or primary intracerebral hemorrhage patients:

- patients who have a clear clinical presentation of either cortical stroke or primary intracerebral hemorrhage confirmed on brain CT. The patients are eligible when the DCE-MRI scans can be performed within 0-6 weeks of the vascular event and on two subsequent days.

Description

Inclusion Criteria:

All subjects:

• Age >18 years old
• The condition of the patient must be well enough to allow participation in the study, which is decided in consultation with the treating physician.

cSVD patients: - patients who present with a transient ischemic attack (TIA) and cSVD related abnormalities on brain MRI. TIA patients are defined as patients with stroke like symptoms that last no longer than 24 hours. MRI abnormalities include extended white matter lesions, (asymptomatic) lacunar infarcts, microbleeds and enlarged Virchow-Robin spaces. The patients are eligible when the first DCE-MRI scan can be performed 8-12 weeks after the TIA to avoid the acute phase, and the second MRI-scan within four weeks after the first.

Cortical stroke or primary intracerebral hemorrhage patients:

- patients who have a clear clinical presentation of either cortical stroke or primary intracerebral hemorrhage confirmed on brain CT. The patients are eligible when the DCE-MRI scans can be performed within 0-6 weeks of the vascular event and on two subsequent days as the vascular permeability may change significantly on the timescale of weeks.

Exclusion Criteria:

All subjects:

• History of cerebrovascular disease (e.g. ischemic/hemorrhagic stroke)
• History of other diseases of the central nervous system (e.g. epilepsy, brain tumor, multiple sclerosis)
• Contra-indications for MRI examination: e.g. pacemaker; neurostimulator; medication pump; cochlear or hearing implant; tattoos or other items that cannot be removed and include metal parts (for instance from operations in the past); metal splinter in the eye; pregnancy and claustrophobia; brain vessel clamps; denture, which contains magnets.
• Contra-indication for MRI contrast agent: e.g. strong suspicion for impaired kidney function (GFR<30ml/min), previous allergic reaction to contrast agent, dialysis patients
• Psychiatric co-morbidity and inability to perform the (DCE-)MRI scans.

cSVD patients

• Patients with a potential cardioembolic source (e.g. atrial fibrillation)
• Stenosis of ≥50% of one or both internal carotid arteries

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cortical stroke or primary intracerebral hemorrhage patients: patients who have a clear clinical presentation of either cortical stroke or primary intracerebral hemorrhage confirmed on brain CT. The patients are eligible when the DCE-MRI scans can be performed within 0-6 weeks of the vascular event and on two subsequent days as the vascular permeability may change significantly on the timescale of weeks.	Procedure: Dynamic contrast enhanced Brain MRI; DCE-MRI is used to quantify the BBB permeability
cSVD patients; patients who present with a transient ischemic attack (TIA) and cSVD related abnormalities on brain MRI. TIA patients are defined as patients with stroke like symptoms that last no longer than 24 hours. MRI abnormalities include extended white matter lesions, (asymptomatic) lacunar infarcts, microbleeds and enlarged Virchow-Robin spaces. The patients are eligible when the first DCE-MRI scan can be performed 8-12 weeks after the TIA to avoid the acute phase, and the second MRI-scan within four weeks after the first.	Procedure: Dynamic contrast enhanced Brain MRI; DCE-MRI is used to quantify the BBB permeability

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pharmacokinetic parameter values Ki and vb	Outcome measures of both days are used to determine the reproducibility of the DCE-MRI method.	day 1 & day 2. Day 2 is min. 24 hours max. 4 weeks after day 1.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pharmacokinetic parameter values: Ki and vb for the retrospectively shortened dynamic scans	The pharmacokinetic parameters are evaluated as a function of scan duration to obtain the shortest scan duration without compromising the reliability of the BBB permeability quantification.	Day 1

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Investigators: Principal Investigator: Cecile RLPN Jeukens, PhD, Maastricht University Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: January 8, 2014
• First Submitted That Met QC Criteria: January 9, 2014
• First Posted (Estimate): January 10, 2014

Study Record Updates

• Last Update Posted (Estimate): October 24, 2016
• Last Update Submitted That Met QC Criteria: October 21, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Cerebral Small Vessel Disease; Blood-Brain Barrier permeability; Dynamic contrast enhanced Magnetic Resonance Imaging; Pharmacokinetic modeling; Reproducibility
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage; Cerebral Small Vessel Diseases
• Other Study ID Numbers: 13-2-036

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No