Revealing molecular subtypes and pathways in large vessel Occlusion stroke: a comprehensive quantitative proteomic analysis

Acute ischemic stroke is the first cause of disability and the second cause of mortality worldwide. In large vessel occlusion (LVO) stroke, the occlusion of cerebral arteries is most caused by a thrombus of arterial (arteriosclerotic, AT) or cardiac (cardioembolic, CAR) origin, although, in some cases the potential cause of occlusion is not clear, and patients are classified as presenting embolic stroke of undetermined source (ESUS). Currently, the LVO stroke diagnosis is based on integration of clinical examinations, neuroimaging analysis and physiologic monitoring, these often fail to determine with high specificity stroke etiology, translating into a lack of treatment plans tailored to the individual patient. Therefore, leveraging on advances on clinical proteomics, it would be valuable to apply translational and precision medicine approaches to move towards more accurate, efficient, and effective treatments. Recently, endovascular therapies, such as mechanical thrombectomy (MT), have demonstrated great benefit regarding long-term clinical outcomes on LVO stroke patients. MT allows the extraction of the occlusive thrombus, providing a unique opportunity to characterize its proteome and thus, to improve our understanding on the molecular mechanisms that drive stroke disease. In recent years, there has been a growing interest in defining a molecular signature of thrombi capable to explain acute ischemic stroke etiology. However, multiple studies attempting this did not find a robust or clinically significant molecular signature.

In this study, we employ a multiplexing depth quantitative proteomics, and unsupervised analysis to profile the proteomic composition of 56 thrombi samples obtained from LVO stroke patients. Our investigation uncovers four distinct thrombi proteomic signatures that transcend stroke aetiology offering insights into specific molecular subtypes and dysregulated pathways, including the upregulation of proteins linked to the acute phase response; the proteasome and catabolism; mitochondrial dysfunction and platelet activation. Our results may open a new way this disease is characterized and subsequently permit the development of new therapies.