Mechanisms of Small Vessel Related Brain Damage and Cognitive Impairment

Neuroimaging in combination with detailed neuropsychological testing has been by far the most fruitful approach to uncover the pleiotropic effects of cerebral small vessel disease (SVD) on the brain and on cognition. This approach has recently been combined with genetics. In this international collaborative effort we hypothesize that CADASIL, a hereditary SVD, and common sporadic forms of SVD have shared mechanisms and that integrating imaging data from both conditions will allow defining key mechanisms of small-vessel related brain damage and associated cognitive impairment. We propose to use our combined patient, family and population-based resources and apply state of the art image post-processing and analytical tools to address the following scientific aims in a collaborative effort: To delineate the mechanisms of incident lacunar infarcts and their consequences on anatomically connected brain regions To identify strategic locations for subcortical ischemic lesions and cognitive performance To explore the mechanisms and clinical impact of cortical changes in patients with SVD. This will include investigations at ultra-high field MRI (7 Tesla) To provide a detailed account of microstructural changes in the normal appearing brain (as seen on conventional MRI) and their imaging and cognitive correlates. This will included diffusion tensor and magnetization transfer imaging and an investigation of the role of iron deposition as a novel marker To provide integrated models predicting cognitive impairment in SVD using multiple imaging markers Our proposal builds on two prospective observational cohorts collected by three of the PIs with longitudinal data already available: 320 patients with CADASIL and documented mutations in the NOTCH3 gene and 820 community-dwelling middle-aged and elderly participants from the Austrian Stroke Prevention Study (ASPS). Both cohorts have received standardized and extensive neuropsychological testing with regular follow-up. The four PIs will each focus on specific questions and apply their methodological tools to both datasets. Using machine learning (ML) processes and the specific expertise provided within the group, data will be integrated into joint models to identify general mechanisms of small vessel related brain damage and cognitive impairment. Validation of the final models will then be possible in external cohorts. By combining our resources and analytical tools we will maximise the chances to achieve our scientific aims. Our ultimate goal will be to provide novel predictive instruments, markers and targets for therapeutic trials.

Cerebral small vessel disease (SVD) is a major cause of stroke and the leading cause of vascular cognitive impairment (VCI). It also contributes to other disabling symptoms such as gait disturbance and late-life depression and its prevalence strongly increases with age. Recent developments in neuroimaging and image post-processing have enabled insights into disease mechanisms and allowed to better identify the spectrum of lesions associated with SVD. Additional insights have come from the study of rare Mendelian variants leading to a disease entity called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL is considered to represent a raw model for sporadic small vessel disease and comparative studies between CADASIL patients and subjects with age-associated cerebral small vessel disease are likely to increase the pathophysiological understanding of this common disorder in elderly individuals. Using data from 320 patients with CADASIL and 820 community-dwelling middle-aged and elderly participants from the Austrian Stroke Prevention Study (ASPS) the MESCOG investigators achieved to identify key pathophysiological mechanisms in SVD and related cognitive impairment. For example, they could demonstrate, that subcortical ischemic lesions (acute infarcts, white matter lesion, lacunes) induce secondary loss of connected grey matter in distant cortex and that this loss of grey matter impacts on cognitive performance. They further provide a more detailed understanding of the pathogenesis of ischemic lesions. Finally, the consortium developed, tested and validated a number of imaging markers for SVD and the ensuing cognitive impairment across different patient populations providing novel biomarkers for use in research and consulting patients in terms of risk prediction and prognosis. Hence, the outcomes from this collaboration are expected to have an impact on both future research activities and patient care.