INflammation and Small Vessel Disease Study

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The INSVD study is a prospective observational cohort study in patients with cerebral small vessel disease (SVD) aimed at examining whether changes in systemic inflammation predict brain white matter damage and cognitive decline. This study is funded by a joint British Heart Foundation and Dutch Heart Foundation research grant. 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.