Biomarkers in Ischemic Stroke and Cerebral Small Vessel Disease

Abstract

The overall aim was to investigate whether biomarkers can improve the understanding and management of ischemic stroke and cerebral small vessel disease (SVD). The studies were based on the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), including 600 ischemic stroke patients aged 18-69 years and matched controls. Patients were followed up after 3 months and cases who were included at the Sahlgrenska University hospital were also invited to a 7-year follow-up, including repeated magnetic resonance imaging (MRI) of the brain. In Paper I, we studied progression of white matter hyperintensities (WMHs), a marker of SVD, over 7 years. Development of clear signs of SVD (marked WMHs) were associated with age and hypertension, and progression with age and marked WMHs at index stroke, but not with vascular risk factors or stroke subtype. In Paper II, we investigated the association between serum neurofilament light chain (NfL) and infarct size, and modeled the temporal course of NfL after stroke. We estimated that NfL peaks at ~34 days after index stroke, and has declined by 50% and 99% at ~3 and ~9 months. At 7 years, NfL associated to both WMH volume and progression. In Paper III, we evaluated plasma brain-derived tau (BD-tau) as a marker of neuronal injury. Acute-phase BD-tau correlated with infarct volume (ρ = 0.72), and adding BD-tau to age and acute neurologic deficit improved prediction of 3-month functional outcome. In Paper IV, we compared inflammatory protein profiles in cryptogenic stroke to large artery atherosclerosis (LAA) stroke. The subtype profiles were very similar both in the acute phase and at the 3-month follow-up, but discriminated both subtypes well from matched controls (AUC ≥ 0.85). Cryptogenic strokes with high atherosclerotic risk were poorly discriminated from LAA (AUC = 0.67), whereas those with a low risk were well discriminated from LAA (AUC = 0.84). In conclusion, imaging markers and serum NfL provide complementary information: imaging captures the accumulated effects of SVD on the brain parenchyma, while NfL reflects recent activity over the preceding months, suggesting it might reduce the need for repeated MRI scans to monitor SVD activity. Circulating levels of NfL and BD-tau correlate with infarct volume, and in particular BD-tau can improve prognostic accuracy. Inflammatory protein profiling may provide clues to the true etiology in subgroups of cryptogenic stroke and help identify patients who could benefit from targeted secondary prevention.