Blood brain barrier permeability in cerebral small vessel disease
Cerebral small vessel disease (SVD) is an enormous public health problem; it represents 20% of ischaemic strokes and is the most common cause of vascular dementia. Understanding of the pathophysiology is nevertheless incomplete and there are no disease-modifying treatments.
Two related novel pathophysiological mechanisms have recently been proposed, namely that inflammation and increased permeability of the blood-brain barrier (BBB) are implicated in the development of SVD. This might mediate the progression from areas of haemodynamic disturbance to the white matter damage seen in the disease.
Cross-sectional MRI studies have shown increased BBB permeability in SVD, and pilot data from Cambridge using positron emission tomography (PET) has shown glial activation (evidence of neuroinflammation) in patients. The key question of whether these processes are causal or merely secondary phenomenon remains uncertain. I will aim to provide further insight into the roles of these process taking blood and CSF samples from patients with SVD and healthy controls who are undergoing combined PET/MRI imaging. I will measure inflammatory markers and the CSF/serum albumin ratio which is the gold standard of quantifying in vivo BBB permeability and examine its relationship with radiological markers of SVD.
This will be complemented by analysis of longitudinal data to determine whether regions of BBB permeability and neuroinflammation progress to tissue damage, as assessed by diffusion tensor imaging (DTI) parameters which are the most sensitive markers of white matter structural damage. These results will build on existing knowledge of the pathophysiology of SVD and potentially inform future options for therapeutic intervention.