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Background and purpose: Cerebral small vessel disease (SVD) is characterized by a wide range of focal and global brain changes. We used automated MRI segmentation to quantify multiple types of SVD brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods: MRI scans of 560 subjects of the Leukoaraiosis and Disability Study (LADIS) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities (WMH), lacunes, cortical infarcts, enlarged perivascular spaces and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results: The strongest predictors of cognitive performance and functional outcome over time were total volumes of WMH, grey matter (GM) and hippocampi (p<0.001 for global cognitive function, processing speed, executive functions and memory; and p<0.001 for poor functional outcome). Volumes of lacunes, cortical infarcts and EVPS were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of WMH, lacunes, GM and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on z-scores strongly predicted cognitive and functional outcomes (p<0.001) even above the contribution of the individual brain changes. Conclusions: Global burden of SVD-related brain changes as quantified by automated image segmentation is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of WMH, lacunar, GM and hippocampal volumes could be used as an imaging identification model of vascular cognitive impairment.

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