Cerebrospinal Fluid Proteomics: Unlocking Pathways in Paediatric Brain Diseases

Abstract

Encephalitis, Aicardi-Goutières syndrome (AGS), and autism spectrum disorder (ASD) are disabling childhood brain conditions. Despite distinct pathophysiology, neuroinflammation may be a converging factor. This study examined the cerebrospinal fluid (CSF) proteome in these conditions: encephalitis as an acquired neuroinflammatory disease, AGS as a monogenic condition, and ASD as an epigenetic disorder. The objectives were to identify biomarkers, define immune profiles, and explore disease mechanisms. CSF was selected due to its proximity to brain parenchyma. Age-matched non-inflammatory neurological controls were used for comparison. Proteomic analysis, performed using Cibacron Blue 3GA beads and mass spectrometry, was followed by multiple reaction monitoring (MRM) for key protein validation. Common dysregulated pathways across the conditions included complement activation, haemostasis, and blood-brain barrier (BBB) disruption, emphasizing immune and vascular involvement in neuroinflammation. Encephalitis samples showed elevated immunoglobulins, complement, and acute phase proteins, suggesting impaired BBB integrity, while glycolytic proteins were reduced, reflecting possible metabolic disruption. AGS samples revealed altered Toll-like receptor (TLR) signalling and upregulation of galectin-3 binding protein, aligning with AGS as an interferonopathy. ASD samples showed synaptic dysregulation, with changes in synaptic proteins such as contactin-2 and neurexin-2, alongside immune changes with decreased immunoglobulins and increased complement proteins. This study highlights the potential of CSF proteomics in uncovering disease mechanisms and identifying biomarkers in neuroinflammatory disorders. Further validation, including plasma proteomics, is necessary to corroborate these findings and broaden understanding of these conditions.