Profiling 92 circulating neurobiological proteins identifies novel candidate biomarkers of long-term cognitive outcome after ischemic stroke

The biological underpinnings of post-stroke cognitive function are largely unknown, and protein investigations can point towards important pathways for further study. We profiled plasma levels of 91 neurology-related proteins (Olink Neurology panel) and serum Neurofilament light chain (NfL) levels in 205 cases in the Sahlgrenska Academy Study on Ischemic Stroke. Blood was sampled in the acute and convalescent (3 months post-stroke) phase. Cognitive outcome was evaluated by the Barrow Neurological Institute Screen for Higher Cerebral Functions 7 years post-stroke. In linear regression models, 6 and 5 proteins in the acute and convalescent phase, respectively, were univariably associated with cognitive outcome at False Discovery Rate (FDR) < 0.05, and 9 and 8 at p < 0.05 after adjustment for age, sex, education and sampling day (model 1) and/or additional adjustment for stroke severity (model 2). Of these, 15 proteins contributed with information in multi-protein models on at least one time-point. These included brain-expressed proteoglycans (NCAN, BCAN, GPC5, SPOCK1); contactin-5 (CNTN5); metabolic enzymes (HAGH, NMNAT1); cluster of differentiation (CD)-proteins (SIGLEC1, CLEC10A, CD200R1); GDNF family receptor alpha-1 (GFR-alpha-1); brorin (VWC2); beta-nerve growth factor (beta-NGF); myostatin (GDF-8); and NfL. We identified novel candidate protein biomarkers of post-stroke cognitive outcome that likely reflect different biological processes, warranting further exploration.