Towards vascular cognitive health: imaging markers of cerebral small vessel disease as mediators of midlife modifiable risk and predictors of later cognitive decline and dementia

• Applicant: Dr. Frauke Beyer
• Subject Area: Human Cognitive and Systems Neuroscience
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464596826

Staying cognitively healthy is of paramount importance when we age. Yet, due to increasing longevity, the prevalence rate of dementia will continue to rise over the coming decades. On the population level, a major pathology underlying dementia is cerebral small vessel disease (cSVD), a disorder of the brain’s small arterioles, capillaries and venules. While often covert and only detectable with magnetic resonance imaging (MRI), a high load of cSVD imaging markers is strongly associated with cognitive impairment and dementia.To date, there is no curative treatment for dementia. Yet, prospective studies and randomized control trials have highlighted that prevention, i.e. modifying lifestyle and cardiovascular risk factors, could significantly reduce dementia incidence. Yet, despite the high prevalence of cSVD in the older population and the increased dementia risk associated with it, we still lack specific preventive strategies for cSVD-related brain injury and concomitant cognitive decline. In this project, I aim to address two key points for the implementation of successful prevention strategies for cognitive decline and dementia in the context of cSVD. First, we need to improve the dementia risk stratification of older individuals with covert cSVD. While a higher cSVD load is statistically associated with cognitive decline, MRI markers of cSVD are present in up to 100% of older participants. Yet, not all develop cognitive impairment and the determinants of progression to dementia are poorly understood. In the first part of this project, I thus aim to predict the risk of individuals for dementia based on the high-dimensional cSVD imaging markers in the brain. In the model, I plan to implement state-of-the art dimension-reduction techniques to extract relevant information from the voxelwise imaging data. Further, I will implement survival analyses, which take into account interval censoring and competing risks to accurately model time to dementia onset. Secondly, we need a better understanding of the role of modifiable risk factors for the emergence of imaging markers of cSVD in midlife. There is ample evidence that midlife is a crucial period for the development of late-life cognitive impairment, and cross-sectional studies have demonstrated correlations between single risk factors, single markers of cSVD and cognition. Yet, relatively little is known about the impact of level and change in modifiable risk factors and the modifying effect of sex on the progression of early imaging markers of cSVD. In the second part of this project, I thus aim to provide a comprehensive description of these mechanisms using elaborate statistical models in a longitudinal cohort. Taken together, I aim to contribute to a better identification of individuals at high dementia risk and an improved understanding of the importance and potential mechanisms of modifiable risk factors in order to tailor preventive strategies for healthy cognitive aging.

• DFG Programme: WBP Fellowship
• International Connection: France
• Participating Institution: Universitätsklinikum Leipzig AöR; Tagesklinik für kognitive Neurologie
• Host: Professorin Dr. Stephanie Debette, Ph.D.