Mechanisms of vascular cognitive impairment in cerebral small vessel disease and stroke

Introduction: Cerebral small vessel disease (CSVD) affects small vessels in the brain and is a major contributor to stroke and vascular cognitive impairment (VCI). Although VCI poses a significant public health burden, the underlying biological processes and mechanisms remain poorly understood. The pursuit of this avenue of research has uncovered several mechanisms of interest including neuroinflammation, blood-brain barrier (BBB) permeability and white matter microstructural damage. This thesis aims to elucidate our understanding of the roles of these mechanisms in CSVD and VCI. Methods: This thesis focusses on two longitudinal studies, the ‘PET-MRI-SVD’ and ‘Rates, risks and routes to reduce vascular dementia’ (R4VaD), which involved a CSVD (n = 77) and stroke (n = 201) cohort respectively. Multimodal neuroimaging data were acquired in both studies, including structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), the latter of which quantifies white matter microstructural integrity. The PET-MRI-SVD study additionally involved dynamic contrast enhanced MRI (DCE-MRI) and positron emission tomography (PET). DCE-MRI was used to quantify BBB permeability whereas the binding potential of 11C-PK11195 radioligand administered during PET scans quantified microglial signal (neuroinflammation). For the PET-MRI-SVD study, the outcome variables were longitudinal progression to VCI, cognitive subdomain scores, and hippocampal and whole-brain atrophy as markers of VCI. The primary outcome variables for the R4VaD study were cognitive and functional assessment scores. Results: Results from the PET-MRI-SVD study revealed that DTI measures, but not neuroinflammation or BBB permeability, predicted progression to VCI over a four-year follow-up in CSVD. However, our analyses of the one-year follow-up cognitive data yielded significant results; neuroinflammation predicted processing speed and long-term memory scores, whereas BBB permeability predicted processing speed scores only. In contrast, DTI measures predicted working memory scores at one year. Furthermore, I demonstrated that neuroinflammation predicted hippocampal atrophy over one year. As for the R4VaD stroke cohort, I did not find associations between any of the DTI measures with cognitive or functional outcomes at one- and two-year follow-up. Conclusion: Our findings suggest that DTI measures may be useful surrogate markers of VCI and that neuroinflammation may contribute to early cognitive decline in CSVD. Furthermore, the results indicate that neuroinflammation may be implicated in hippocampal atrophy at the early stages of the CSVD trajectory. These findings highlight the necessity to further investigate the biological mechanisms linking cerebrovascular disease and VCI with the goal of identifying therapeutic targets to delay CSVD progression and mitigate its effects.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Zainurin, Adriana

Advisor dc:contributor.advisor

• Markus, Hugh

• Blood-brain barrier permeability
• Cerebral small vessel disease
• Diffusion tensor imaging
• Magnetic resonance imaging
• Neuroinflammation
• Positron emission tomography
• Stroke
• Vascular cognitive impairment
• Vascular dementia
• White matter damage

Licence

• https://www.repository.cam.ac.uk/bitstreams/07ef87be-b9fc-457a-8072-1a82b9a5cbb0/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.123525

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/393022