Study Results
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Basic Information
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RECRUITING
200 participants
OBSERVATIONAL
2022-08-10
2026-07-31
Brief Summary
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Detailed Description
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STUDY DESIGN ---------------------------------------------
This study will be conducted at the University of Cambridge (UK) and Radboud University Medical Centre (Nijmegen, Netherlands) with 100 of the 200 total participants recruited at each site.
For the Cambridge arm of the study, patients will be recruited from the clinical stroke service at Cambridge University Hospitals NHS Foundation Trust. Patients will be identified by Professor Hugh Markus (Principal Investigator), Dr Stefania Nannoni and other doctors from their clinics. For the Nijmegen arm, participants will initially be recruited from the RUN DMC cohort, and supplemented with patients from the outpatient clinic of the Neurology department of Radboud University Medical Centre. Patients will be identified by Professor Frank-Erik de Leeuw (Principal Investigator) and other doctors from their clinics. At both sites, electronic hospital records will be used to aid screening and eligibility assessments. In Nijmegen, an ECG and duplex of the carotid arteries are carried out as part of the screening procedure, since data on atrial fibrillation and large artery disease are not always up-to-date or readily available from medical records. Clinicians will check the clinical information and check eligibility against the study criteria. Stroke Research Nurses and Study Coordinators will assist in patient recruitment and receiving consent and collection of baseline data.
Investigators and researchers will ensure that each trial participant is fully informed about the nature and objectives of the trial, and possible risks associated with their participation. Participants will be provided with a Participant Information Sheet explaining the rationale and nature of the study, study procedures and potential benefits and risks of taking part. They will be given an opportunity to ask questions about the study.
Phlebotomy and clinical assessment and cognitive testing will take place in the stroke clinic setting. MRI scanning will be done on identical scanners at the Wolfson Brain Imaging Centre, University of Cambridge, and at the Radiology department of Radboud University Medical Centre.
* At baseline, subjects will undergo clinical assessment, neurological and cardiovascular examination, cognitive testing, motor assessment, blood taking for immune phenotyping and MRI brain.
* At 2 years, subjects will undergo clinical assessment, neurological and cardiovascular examination, cognitive testing, motor assessment, and MRI brain.
We will continue to follow-up subjects every two years with clinical and cognitive assessments to determine the presence or absence of stroke and dementia for 6 years, via separate funding.
AIMS AND HYPOTHESIS ---------------------------------------------
Our overarching aim is to identify specific components of the dysregulated immune response in SVD, which relate to disease progression, and can be targeted by specific therapeutic interventions. The study hypothesis is that long-term activation of the immune system, subsequent blood brain barrier (BBB) leakage and chronic neuroinflammation initiates and accelerates SVD, which compromises structural and functional brain integrity, leading to progressive white matter damage and accelerates vascular cognitive impairment. We propose an integrative approach, combining comprehensive immunophenotyping of the peripheral blood immune compartment with advanced neuroimaging biomarkers of SVD, and blood brain barrier permeability.
To test our hypothesis, we will address the following key research questions:
1. Does immune reprogramming, determined by detailed immune phenotpying in the peripheral circulation, predict white matter damage in SVD and its progression?
2. What are the relationships between systemic immune changes in SVD, and BBB leakage?
OBJECTIVES ---------------------------------------------
Primary objectives:
* To determine whether changes in immune cell function and phenotype identified in the systemic circulation predict disease progression in SVD, as measured by diffusion tensor imaging (DTI)-MRI
* To determine the pattern of systemic immune changes which occur in SVD
* To determine whether this pattern predicts disease progression, as measured by white matter damage on DTI
Secondary objectives:
* To characterise the alteration in immune phenotype occurring in SVD and how these relate to clinical, neurocognitive and imaging parameters.
* To determine the relationships between systemic immune changes in SVD, and BBB leakage.
Conditions
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Study Design
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COHORT
PROSPECTIVE
Study Groups
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INSVD Cohort
200 patients with cerebral small vessel disease - 100 recruited from Cambridge, UK; 100 recruited from Nijmegen, Netherlands.
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* Be aged 40 years and over
* Have symptomatic cerebral small vessel disease (SVD) defined as:
* Clinical lacunar stroke syndrome with lacunar infarct, as defined by the Standards for Reporting Vascular Changes on Neuroimaging (STRIVE) criteria
* And/OR Symptoms of cognitive impairment due to SVD with lacunar infarct on MRI
* And/OR Gait apraxia/motor impairment presumed due to SVD with lacunar infarct on MRI
Exclusion Criteria
* Contraindications to taking part in MRI study as assessed by the local MRI safety questionnaire, e.g., pacemaker
* Vaccination or infection with fever in preceding month
* Any stroke cause other than SVD including:
* Cardioembolic source
* Carotid or vertebral stenosis \> 50% measured on NASCET (North American Symptomatic Carotid Endarterectomy Trial) criteria
* Myocardial infarction in past year
* Auto-immune/auto-inflammatory disease
* Use of immunomodulating drugs
* Estimated glomerular filtration rate (eGFR) =\<59 ml/min/1.73m2 within past 3 months for Cambridge, and eGFR =\<29 ml/min/1.73m2 within past 3 months for Nijmegen, in line with local guidelines. Estimated GFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation: 186 x (Creatinine / 88.4)-1.154 x (Age)- 0.203 x (0.742 if female) x (1.210 if black). Creatinine will be checked within 3 months of the MRI, and if this has not been done as part of clinical care it will be performed as a research procedure.
* Another diagnosed chronic neurological condition (e.g. Alzheimer's, Parkinson's disease, motor neurone disease, multiple sclerosis).
* Limited life expectancy due to another illness or chronic condition making the 2-year follow-up difficult (e.g. widespread malignancy).
* Known monogenic cause of small vessel disease (e.g. CADASIL - Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy)
40 Years
ALL
No
Sponsors
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Radboud University Medical Center
OTHER
Wolfson Brain Imaging Centre
UNKNOWN
University of Cambridge
OTHER
Responsible Party
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Hugh Markus
Principal Investigator
Principal Investigators
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Hugh S Markus
Role: PRINCIPAL_INVESTIGATOR
University of Cambridge
Locations
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Radboud University Medical Centre
Nijmegen, , Netherlands
University of Cambridge
Cambridge, Cambridgeshire, United Kingdom
Countries
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Central Contacts
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Facility Contacts
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References
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Low A, van Winden S, Cai L, Kessels RPC, Maas MC, Morris RG, Nus M, Tozer DJ, Tuladhar A, van der Kolk A, Wolters R, Mallat Z, Riksen NP, Markus H, de Leeuw FE. Immune regulation and blood-brain barrier permeability in cerebral small vessel disease: study protocol of the INflammation and Small Vessel Disease (INSVD) study - a multicentre prospective cohort study. BMJ Open. 2024 Feb 26;14(2):e084303. doi: 10.1136/bmjopen-2024-084303.
Related Links
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Other Identifiers
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22/EE/00141
Identifier Type: OTHER
Identifier Source: secondary_id
312747
Identifier Type: OTHER
Identifier Source: secondary_id
A096290
Identifier Type: -
Identifier Source: org_study_id
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