Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination

Background and objectives New onset persistent headache has been reported following acute COVID-19 and to some degree also after SARS-CoV-2 vaccination. The mechanisms for these headache types are unclear. The purpose of this study was to assess levels of amyloid related biomarkers in patients with persistent headache after COVID-19 and SARS-CoV-2 vaccine. Methods In this prospective observational cohort, patients with severe headache as the dominating symptom after COVID-19 (n=29) and SARS-CoV-2 vaccination (n=31), had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured by ELISA in relation to levels in healthy controls (n=16). Results We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared to the two other groups. At both inclusion and after 6 months APP levels were also increased in those with accompanying cognitive symptoms. In contrast, plasma levels of PZP were elevated in patients with headache after SARS-CoV-2 vaccination at both inclusion and after 6 months as compared to healthy controls. CTSL was only elevated in those with COVID-19 associated as compared with those with vaccine associated headache at baseline, whereas SAA1 showed levels comparable in all groups. Conclusion Altered plasma levels of soluble markers potentially reflecting changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 where we also found some association with cognitive symptoms. NCT04576351 NCT05235776 What is already known on this topic New onset persistent headache occurs in a subset of individuals after COVID-19 and to some extent after SARS-CoV-2 vaccine. However, the pathophysiological mechanisms are unknown. What this study adds Altered plasma levels of soluble markers that potentially could reflect changes in amyloid processing was found in patients with persistent headache after SARS-CoV-2 vaccine and particular in those with persistent headache after COVID-19 with association to cognitive symptoms. How this study might affect research, practice or policy Our data underscore the need for more long-time follow-up of patients with new onset headache following COVID-19 or SARS-CoV-2 vaccination and this follow-up might also include blood tests for amyloid processing and neuroinflammation.