Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations
Keller, J. N.; Radabaugh, H.; Karvelas, N.; Fitzsimons, S.; Treiman, S.; Palafox, M. F.; McDonnell, L.; Quiroz, Y. T.; Lopera, F. J.; Banerjee, D.; Wang, M. M.; Arboleda-Velasquez, J. F.; Meschia, J. F.; Ferguson, A. R.; Elahi, F. M.
Show abstract
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of vascular cognitive impairment and dementia. A genetic arteriolosclerotic disease, the molecular mechanisms driving vascular brain degeneration and decline remain unclear. With the goal of driving discovery of disease-relevant biological perturbations in CADASIL, we used machine learning approaches to extract proteomic disease signatures from large-scale proteomics generated from plasma collected from three distinct cohorts in US and Colombia: CADASIL-Early (N = 53), CADASIL-Late (N = 45), and CADASIL-Colombia (N = 71). We extracted molecular signatures with high predictive value for early and late-stage CADASIL and performed robust cross- and external-validation. We examined the biological and clinical relevance of our findings through pathway enrichment analysis and testing of associations with clinical outcomes. Our study represents a model for unbiased discovery of molecular signatures and disease biomarkers, combining non-invasive plasma proteomics with clinical data. We report on novel disease-associated molecular signatures for CADASIL, derived from the accessible plasma proteome, with relevance to vascular cognitive impairment and dementia.
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