Imaging markers of cerebral small vessel disease

Vascular cognitive impairment (VCI) is the second most common cause of cognitive impairment in the elderly population and it very often co-occurs with impairment resulting from other neurodegenerative pathologies. Cognitive impairment due to vascular pathology is potentially treatable; i.e. the progression could be slowed or even stopped by managing the underlying vascular disease. However, there is no specific treatment available for VCI up to date. One of the main reasons for this is an insufficient understanding of the disease pathophysiology. Cerebral small vessel disease is the primary pathology leading to VCI and therefore its study provides the chance to elucidate the mechanisms leading from vascular pathology to cognitive impairment. Understanding the underlying disease mechanisms is crucial for diagnosis, prevention and managing the disease. For this purpose, markers play an important role, as they indicate which disease processes are at play within the brain. This PhD-work aimed at finding optimal imaging markers for diagnosing cerebral small vessel diseases and estimating the vascular disease burden in the brain. Advances in brain imaging tools, in particular diffusion tensor imaging (DTI), have enabled the exploration of microstructural changes in the human brain, which precede the occurrence of lesions that are visible on conventional MRI. The first project focused on developing and establishing a DTI-based imaging marker for small vessel disease that is quantitative, reliable, and fully automated. This marker (peak width of skeletonized mean diffusivity, PSMD) was then systematically investigated - along with conventional imaging markers - in patients with hereditary and sporadic SVD, memory clinic patients as well as in patients with Alzheimer pathology. The results showed that PSMD outperformed the conventional markers in explaining the cognitive impairment scores. Furthermore, in longitudinal analysis, PSMD was more sensitive to disease related changes than any other imaging markers, which resulted in low sample size estimations for a hypothetical clinical trial. Additionally. PSMD showed very high interscanner reproducibility suggesting that it might be especially useful in multicenter studies. Interestingly, increases in PSMD were mostly linked to vascular but not to neurodegenerative disease. Therefore, PSMD could be a valuable tool to disentangle effects caused by these different pathologies, a common challenge in understanding cognitive impairment. This suggests that the newly established marker PSMD could be easily applied to large samples and may be of great utility for both research studies and clinical use. The second project focused on the evaluation of cortical superficial siderosis (cSS) as a potential new marker for cerebral small vessel diseases. cSS emerged recently as a marker for cerebral amyloid angiopathy (CAA). However, the presence of cSS is associated with many other signs of cSVD, such as cerebral microbleeds (CMB) and white matter hyperintensities (WMH), and therefore its specificity for CAA was questionable. The results of the second project revealed that the distribution patterns and frequency of CMB and WMH overlap between different subtypes of cSVD. This clearly demonstrated that these imaging features have limited discriminative value. More importantly, the presence of cSS was found to be strongly indicative of CAA. To summarize, the key findings reported in this PhD-work have important implications for diagnosing patients with cerebral small vessel disease, disentangling underlying pathologies, as well as for managing and treating the disease. The newly established imaging marker PSMD can be utilized to select the target population for clinical studies and may function as a surrogate marker for treatment effects. PSMD can be further used to identify patients who have a low disease burden as targets for prevention and early treatment.