Abstract
<jats:p>Cerebral small vessel disease (SVD) is a major cause of stroke, cognitive impairment, and dementia, yet its underlying mechanisms remain poorly understood. Most existing research has focused on older individuals with advanced SVD, leaving early pathological changes unexplored. This thesis aimed to investigate early brain alterations associated with SVD in young and middle-aged adults with hypertension, the main risk factor for SVD, and to examine the role of blood pressure fluctuations in SVD progression. Using data from the prospective Hyperintense study, we showed that young adults with hypertension already exhibit subtle MRI markers of SVD, including increased white matter hyperintensity burden. We further demonstrated that these patients have impaired blood-brain barrier (BBB) integrity independent of existing MRI lesions, suggesting BBB dysfunction as an early feature of SVD. Blood pressure increases were associated with increased BBB leakage, indicating that BBB integrity is dynamic and influenced by blood pressure changes. In addition, BBB leakage was associated with reduced white matter microstructural integrity. Finally, in participants with established SVD, higher visit-to-visit blood pressure variability was associated with faster progression of white matter damage and increased risk of incident lacunes over 14 years. Together, these findings highlight BBB dysfunction as a potential early mechanism and therapeutic target in SVD.</jats:p>